Lactam compounds useful as protein kinase inhibitors

ABSTRACT

The present invention provides novel compounds useful as inhibitors of protein kinases. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various diseases.

PRIORITY CLAIM

The present application is a divisional of U.S. patent application Ser.No. 11/242,413, filed Oct. 3, 2005 (pending), which claims the benefitof U.S. Provisional Application Ser. No. 60/615,761, filed Oct. 4, 2004.The entire contents of each of the above-referenced patent applicationsare incorporated herein by this reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to inhibitors of protein kinases. Theinvention also provides pharmaceutical compositions comprising thecompounds of the invention and methods of using the compositions in thetreatment of various diseases.

2. Background of the Invention

Protein kinases constitute a large family of structurally relatedenzymes that effect the transfer of a phosphate group from a nucleosidetriphosphate to a protein acceptor. A vast array of cellular functions,including DNA replication, cell cycle progression, energy metabolism,and cell growth and differentiation, are regulated by reversible proteinphosphorylation events mediated by protein kinases. Additionally,protein kinase activity has been implicated in a number of diseasestates. Accordingly, protein kinase targets have attracted substantialdrug discovery efforts in recent years, with several protein kinaseinhibitors achieving regulatory approval (reviewed in Fischer, Curr.Med. Chem., 11:1563 (2004); Dancey and Sausville, Nature Rev. DrugDisc., 2:296 (2003)).

Mitosis is a stage in the cell cycle during which a series of complexevents ensure the fidelity of chromosome separation into two daughtercells. Several current cancer therapies, including the taxanes and vincaalkaloids, act to inhibit the mitotic machinery. Mitotic progression islargely regulated by proteolysis and by phosphorylation events that aremediated by mitotic kinases. Aurora kinase family members (e.g., AuroraA, Aurora B, Aurora C) regulate mitotic progression through modulationof centrosome separation, spindle dynamics, spindle assembly checkpoint,chromosome alignment, and cytokinesis (Dutertre et al., Oncogene, 21:6175 (2002); Berdnik et al., Curr. Biol., 12: 640 (2002)).Overexpression and/or amplification of Aurora kinases have been linkedto oncogenesis in several tumor types including those of colon andbreast (Warner et al., Mol. Cancer Ther., 2: 589 (2003); Bischoff etal., EMBO, 17: 3062 (1998); Sen et al., Cancer Res., 94: 1320 (2002)).Moreover, Aurora kinase inhibition in tumor cells results in mitoticarrest and apoptosis, suggesting that these kinases are importanttargets for cancer therapy (Ditchfield, J. Cell Biol., 161: 267 (2003);Harrington et al., Nature Med., 1 (2004)). Given the central role ofmitosis in the progression of virtually all malignancies, inhibitors ofthe Aurora kinases are expected to have application across a broad rangeof human tumors.

PLK is a serine/threonine protein kinase that plays a key role in cellcycle control. PLK controls entry and progression through mitosis atmultiple stages by regulating centrosome maturation, activation ofinitiating factors, degradation of inhibitory components, chromosomecondensation, and exit from mitosis (reviewed in Barr et al., NatureReviews Mol Cell Biol., 5; 429 (2004)). PLK has been reported to beoverexpressed in numerous cancers such as melanoma, ovarian, colorectal,lung and squamous cell carcinoma of the head and neck. Increased levelsof expression are additionally correlated with poor prognosis andsurvival. (Kneisel et al., J Cutan Pathol 29: 354 (2002); Takai et al.Cancer Lett 164: 41 (2001); Takahashi et al Cancer Sci.; 94(2):148(2003); Wolf et al. Oncogene 14: 543 (1997); Knecht et al. Cancer Res.59 (1999)). Overexpression of the kinase transforms cells, renderingthem oncogenic such that they acquire the ability to form tumors in mice(Smith et al., Biochem. Biophys. Res. Commun. 234; 397 (1997)). PLKprotein levels are also elevated in tumor relative to normal cell linesin culture. Downregulation of PLK protein expression by RNA interferencein tumor cell lines results in a reduction of cell proliferation,mitotic arrest at prometaphase and the rapid progression into apoptosis(Spankuch-Schmitt et al. J. Natl. Cancer Inst. 94(24):1863 (2002);Spankuch-Schmitt et al. Oncogene 21(20):3162 (2002)). This effect wasnot observed in normal cell lines. Moreover downregulation of PLK byshort hairpin expression in mice with human xenografts reduced tumorgrowth to 18% (Spankuch B et al. (2004) J. Natl. Cancer Inst.96(11):862-72). The key role of PLK in mitotic progression, itsoverexpression in a wide range of malignancies and theanti-proliferative effect observed upon its inhibition demonstrate itsfeasibility as a therapeutic target.

Anti-mitotic drugs that bind to tubulin (taxanes and vinca alkaloids)are currently utilized as chemotherapeutic drugs. Tubulin regulatescellular processes outside of mitosis therefore these drugs offer noselectivity towards cancer cells and are toxic to normal cells. Smallmolecule inhibitors that target the mitotic process specifically bytargeting kinases that are overexpressed and active only in rapidlyproliferating mitotic cells, such as PLK and Aurora kinase, may beclinically effective against tumors and not constrained by dose-limitingtoxicities.

Cell cycle checkpoints are regulatory pathways that control the orderand timing of cell cycle transitions. They ensure that critical eventssuch as DNA replication and chromosome segregation are completed in highfidelity. The regulation of these cell cycle checkpoints is a criticaldeterminant of the manner in which tumor cells respond to manychemotherapies and radiation. Many effective cancer therapies work bycausing DNA damage; however, resistance to these agents remains asignificant limitation in the treatment of cancer. One importantmechanism leading to drug resistance is the activation of a checkpointpathway that arrests the cell cycle to provide time for repair andinduces the transcription of genes that facilitate repair. Cell cycleprogression is prevented, and immediate cell death of the damaged cellis avoided. By abrogating such checkpoint arrests at, for example, theG2 checkpoint, it may be possible to synergistically augment the tumorcell death induced by DNA damage and to circumvent resistance. (Shyjanet al., U.S. Pat. No. 6,723,498 (2004)). Human Chk-1 plays a role inregulating cell cycle arrest by phosphorylating the phosphatase cdc25 onSerine 216, thereby preventing the activation of cdc2/cyclin B and theinitiation of mitosis. (Sanchez et al., Science, 277:1497 (1997)).Therefore, inhibition of Chk-1 should enhance the effect of DNA damagingagents by initiating mitosis before DNA repair is complete, therebypromoting tumor cell death.

Accordingly, there is a need to develop inhibitors of protein kinases,including Chk-1, Aurora, and PLK. Such inhibitors are useful fortreating various diseases or conditions associated with protein kinaseactivity, and are especially needed in view of the inadequate treatmentscurrently available for many of these disorders.

DESCRIPTION OF THE INVENTION

The present invention provides compounds that are effective inhibitorsof protein kinases, including Chk-1, Aurora kinase, and PLK. Thesecompounds are useful for inhibiting kinase activity in vitro and invivo, and are especially useful for the treatment of various cellproliferative diseases.

The compounds of the invention are represented by formula (I):

or a pharmaceutically acceptable salt thereof;wherein:

-   Ring A is an optionally substituted 5- or 6-membered aryl or    heteroaryl ring;-   G¹ is C═O, C═S, or S(═O)₂;-   Y¹ is N or CH and Y² is N or CR⁷, provided that at least one of Y¹    and Y² is N;-   R^(a) is hydrogen, —C(O)R^(5a), —C(O)N(R^(4a))₂, —CO₂R^(6a),    —SO₂R^(6a), —SO₂N(R^(4a))₂, an optionally substituted C₁₋₁₀    aliphatic, or an optionally substituted aryl, heteroaryl, or    heterocyclyl ring;-   R^(b) is hydrogen or an optionally substituted aliphatic, aryl,    heteroaryl, or heterocyclyl group;-   R^(c) is hydrogen, fluoro, —OR⁵, —N(R⁴)₂, or an optionally    substituted C₁₋₄ aliphatic;-   R^(d) is hydrogen, fluoro, C₁₋₄ aliphatic, or C₁₋₄ fluoroaliphatic;    or R^(c) and R^(d), taken together with the carbon atom to which    they are attached, form an optionally substituted 3- to 6-membered    carbocyclic ring;-   R^(e) is hydrogen, halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵,    —C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R¹⁰, —OR⁵, —N(R⁴)₂, —NR⁴C(O)R⁵,    —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —CO₂R⁵, —C(O)R⁵, —C(O)N(R⁴)₂,    —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, or an optionally substituted C₄    aliphatic;-   each R³ independently is selected from the group consisting of C₁₋₃    aliphatic, -fluoro, —OH, and —O(C₁₋₃ alkyl), or two substituents R³    on the same carbon atom, taken together with the carbon atom to    which they are attached, form a 3- to 6-membered carbocyclic ring;-   each R⁴ independently is hydrogen or an optionally substituted    aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R⁴ on the    same nitrogen atom, taken together with the nitrogen atom, form an    optionally substituted 3-to-membered heterocyclyl ring having, in    addition to the nitrogen atom, 0-2 ring heteroatoms selected from N,    O, and S;-   each R^(4a) independently is hydrogen or an optionally substituted    aliphatic, aryl, heteroaryl, or heterocyclyl group; or two R^(4a) on    the same nitrogen atom, taken together with the nitrogen atom, form    an optionally substituted 4- to 8-membered heterocyclyl ring having,    in addition to the nitrogen atom, 0-2 ring heteroatoms selected from    N, O, and S;-   each R⁵ independently is hydrogen or an optionally substituted    aliphatic, aryl, heteroaryl, or heterocyclyl group;-   each R^(5a) independently is hydrogen or an optionally substituted    aliphatic, aryl, heteroaryl, or heterocyclyl group;-   each R⁶ independently is an optionally substituted aliphatic or aryl    group;-   each R^(6a) independently is an optionally substituted aliphatic or    aryl group; and-   R¹⁰ is —CO₂R⁵ or —C(O)N(R⁴)₂.

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. Terms used herein shall be accorded the followingdefined meanings, unless otherwise indicated.

The term “aliphatic” or “aliphatic group”, as used herein, means asubstituted or unsubstituted straight-chain, branched or cyclic C₁₋₁₂hydrocarbon, which is completely saturated or which contains one or moreunits of unsaturation, but which is not aromatic. For example, suitablealiphatic groups include substituted or unsubstituted linear, branchedor cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof, such as(cylcoalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Invarious embodiments, the aliphatic group has 1 to 12, 1 to 8, 1 to 6, 1to 4, or 1 to 3 carbons.

The terms “alkyl”, “alkenyl”, and “alkynyl”, used alone or as part of alarger moiety, refer to a straight and branched chain aliphatic grouphaving from 1 to 12 carbon atoms. For purposes of the present invention,the term “alkyl” will be used when the carbon atom attaching thealiphatic group to the rest of the molecule is a saturated carbon atom.However, an alkyl group may include unsaturation at other carbon atoms.Thus, alkyl groups include, without limitation, methyl, ethyl, propyl,allyl, propargyl, butyl, pentyl, and hexyl.

For purposes of the present invention, the term “alkenyl” will be usedwhen the carbon atom attaching the aliphatic group to the rest of themolecule forms part of a carbon-carbon double bond. Alkenyl groupsinclude, without limitation, vinyl, 1-propenyl, 1-butenyl, 1-pentenyl,and 1-hexenyl.

For purposes of the present invention, the term “alkynyl” will be usedwhen the carbon atom attaching the aliphatic group to the rest of themolecule forms part of a carbon-carbon triple bond. Alkynyl groupsinclude, without limitation, ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl,and 1-hexynyl.

The term “cycloaliphatic”, used alone or as part of a larger moiety,refers to a saturated or partially unsaturated cyclic aliphatic ringsystem having from 3 to about 14 members, wherein the aliphatic ringsystem is optionally substituted. In some embodiments, thecycloaliphatic is a monocyclic hydrocarbon having 3-8 or 3-6 ring carbonatoms. Nonlimiting examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl,cycloheptenyl, cyclooctyl, cyclooctenyl, and cyclooctadienyl. In someembodiments, the cycloaliphatic is a bridged or fused bicyclichydrocarbon having 6-12, 6-10, or 6-8 ring carbon atoms, wherein anyindividual ring in the bicyclic ring system has 3-8 members.

In some embodiments, two adjacent substituents on the cycloaliphaticring, taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 3- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the term “cycloaliphatic” includesaliphatic rings that are fused to one or more aryl, heteroaryl, orheterocyclyl rings. Nonlimiting examples include indanyl,5,6,7,8-tetrahydro-quinoxalinyl, decahydronaphthyl, ortetrahydronaphthyl, where the radical or point of attachment is on thealiphatic ring. The term “cycloaliphatic” may be used interchangeablywith the terms “carbocycle”, “carbocyclyl”, “carbocyclo”, or“carbocyclic”.

The terms “aryl” and “ar-”, used alone or as part of a larger moiety,e.g., “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refer to a C₆ to C₁₄aromatic hydrocarbon, comprising one to three rings, each of which isoptionally substituted. Preferably, the aryl group is a C₆₋₁₀ arylgroup. Aryl groups include, without limitation, phenyl, naphthyl, andanthracenyl. In some embodiments, two adjacent substituents on the arylring, taken together with the intervening ring atoms, form an optionallysubstituted fused 5- to 6-membered aromatic or 4- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the term “aryl”, as used herein,includes groups in which an aromatic ring is fused to one or moreheteroaryl, cycloaliphatic, or heterocyclyl rings, where the radical orpoint of attachment is on the aromatic ring. Nonlimiting examples ofsuch fused ring systems include indolyl, isoindolyl, benzothienyl,benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl,quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl,phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, fluorenyl,indanyl, phenanthridinyl, tetrahydronaphthyl, indolinyl, phenoxazinyl,benzodioxanyl, and benzodioxolyl. An aryl group may be mono-, bi-, tri-,or polycyclic, preferably mono-, bi-, or tricyclic, more preferablymono- or bicyclic. The term “aryl” may be used interchangeably with theterms “aryl group”, “aryl moiety”, and “aryl ring”.

An “aralkyl” or “arylalkyl” group comprises an aryl group covalentlyattached to an alkyl group, either of which independently is optionallysubstituted. Preferably, the aralkyl group is C₆₋₁₀ aryl(C₁₋₆)alkyl,C₆₋₁₀ aryl(C₁₋₄)alkyl, or C₆₋₁₀aryl(C₁₋₃)alkyl, including, withoutlimitation, benzyl, phenethyl, and naphthylmethyl.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., heteroaralkyl, or “heteroaralkoxy”, refer to groupshaving 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having6, 10, or 14 π electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to four heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. In some embodiments, twoadjacent substituents on the heteroaryl, taken together with theintervening ring atoms, form an optionally substituted fused 5- to6-membered aromatic or 4- to 8-membered non-aromatic ring having 0-3ring heteroatoms selected from the group consisting of O, N, and S.Thus, the terms “heteroaryl” and “heteroar-”, as used herein, alsoinclude groups in which a heteroaromatic ring is fused to one or morearyl, cycloaliphatic, or heterocyclyl rings, where the radical or pointof attachment is on the heteroaromatic ring. Nonlimiting examplesinclude indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl,indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl,carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, andpyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group may be mono-,bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, morepreferably mono- or bicyclic. The term “heteroaryl” may be usedinterchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or“heteroaromatic”, any of which terms include rings that are optionallysubstituted. The term “heteroaralkyl” refers to an alkyl groupsubstituted by a heteroaryl, wherein the alkyl and heteroaryl portionsindependently are optionally substituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 3- to 7-membered monocyclic, or to a fused 7- to 10-membered orbridged 6- to 10-membered bicyclic heterocyclic moiety that is eithersaturated or partially unsaturated, and having, in addition to carbonatoms, one or more, preferably one to four, heteroatoms, as definedabove. When used in reference to a ring atom of a heterocycle, the term“nitrogen” includes a substituted nitrogen. As an example, in aheterocyclyl ring having 1-3 heteroatoms selected from oxygen, sulfur ornitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (asin pyrrolidinyl) or ⁺NR (as in N-substituted pyrrolidinyl). Aheterocyclic ring can be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure, and any of the ringatoms can be optionally substituted. Examples of such saturated orpartially unsaturated heterocyclic radicals include, without limitation,tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl.

In some embodiments, two adjacent substituents on a heterocyclic ring,taken together with the intervening ring atoms, for an optionallysubstituted fused 5- to 6-membered aromatic or 3- to 8-memberednon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S. Thus, the terms “heterocycle”,“heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclicmoiety”, and “heterocyclic radical”, are used interchangeably herein,and include groups in which a heterocyclyl ring is fused to one or morearyl, heteroaryl, or cycloaliphatic rings, such as indolinyl,3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherethe radical or point of attachment is on the heterocyclyl ring. Aheterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by aheterocyclyl, wherein the alkyl and heterocyclyl portions independentlyare optionally substituted.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond between ring atoms. Theterm “partially unsaturated” is intended to encompass rings havingmultiple sites of unsaturation, but is not intended to include aryl orheteroaryl moieties, as herein defined.

The terms “haloaliphatic”, “haloalkyl”, “haloalkenyl” and “haloalkoxy”refer to an aliphatic, alkyl, alkenyl or alkoxy group, as the case maybe, which is substituted with one or more halogen atoms. As used herein,the term “halogen” or “halo” means F, Cl, Br, or I. The term“fluoroaliphatic” refers to a haloaliphatic wherein the halogen isfluoro.

The term “linker group” or “linker” means an organic moiety thatconnects two parts of a compound. Linkers typically comprise an atomsuch as oxygen or sulfur, a unit such as —NH—, —CH₂—, —C(O)—, —C(O)NH—,or a chain of atoms, such as an alkylene chain. The molecular mass of alinker is typically in the range of about 14 to 200, preferably in therange of 14 to 96 with a length of up to about six atoms. In someembodiments, the linker is a C₁₋₆ alkylene chain.

The term “alkylene” refers to a bivalent alkyl group. An “alkylenechain” is a polymethylene group, i.e., —(CH₂)_(n)—, wherein n is apositive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylenegroup in which one or more methylene hydrogen atoms is replaced with asubstituent. Suitable substituents include those described below for asubstituted aliphatic group. An alkylene chain also may be substitutedat one or more positions with an aliphatic group or a substitutedaliphatic group.

An alkylene chain also can be optionally interrupted by a functionalgroup. An alkylene chain is “interrupted” by a functional group when aninternal methylene unit is replaced with the functional group. Examplesof suitable “interrupting functional groups” include —C(R*)═C(R*)—,—C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —S(O)₂N(R⁺)—, —N(R*)—, —N(R⁺)CO—,—N(R⁺)C(O)N(R⁺)—, —N(R⁺)CO₂—, —C(O)N(R⁺)—, —C(O)—, —C(O)—C(O)—, —CO₂—,—OC(O)—, —OC(O)O—, —OC(O)N(R⁺)—, —C(NR⁺)═N, —C(OR*)═N—, —N(R⁺)—N(R⁺)—,or —N(R⁺)S(O)₂—. Each R⁺, independently, is hydrogen or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group, or twoR⁺ on the same nitrogen atom, taken together with the nitrogen atom,form a 5-8 membered aromatic or non-aromatic ring having, in addition tothe nitrogen atom, 0-2 ring heteroatoms selected from N, O, and S. EachR* independently is hydrogen or an optionally substituted aliphatic,aryl, heteroaryl, or heterocyclyl group.

Examples of C₃₋₆ alkylene chains that have been “interrupted” with —O—include —CH₂OCH₂—, —CH₂O(CH)₂—, —CH₂O(CH₂)₃—, —CH₂O(CH)₄—, —(CH₂)₂OCH₂—,—(CH₂)₂O(CH₂)₂—, —(CH₂)₂O(CH₂)₃—, —(CH₂)₃O(CH₂)—, —(CH₂)₃O(CH₂)₂—, and—(CH₂)₄O(CH₂)—. Other examples of alkylene chains that are “interrupted”with functional groups include —CH₂ZCH₂—, —CH₂Z(CH₂)₂—, —CH₂Z(CH₂)₃—,—CH₂Z(CH₂)₄—, —(CH₂)₂ZCH₂—, —(CH₂)₂Z(CH₂)₂—, —(CH₂)₂Z(CH₂)₃—,—(CH₂)₂Z(CH₂)—, —(CH₂)₂Z(CH₂)₂—, and —(CH₂)₄Z(CH₂)—, wherein Z is one ofthe “interrupting” functional groups listed above.

One of ordinary skill in the art will recognize that when an alkylenechain having an interruption is attached to a functional group, certaincombinations are not sufficiently stable for pharmaceutical use. Onlystable or chemically feasible compounds are within the scope of thepresent invention. A stable or chemically feasible compound is one inwhich the chemical structure is not substantially altered when kept at atemperature from about −80° C. to about +40° C., preferably from about−20° C. to about +40° C., in the absence of moisture or other chemicallyreactive conditions, for at least a week, or a compound which maintainsits integrity long enough to be useful for therapeutic or prophylacticadministration to a patient.

The term “substituted”, as used herein, means that a hydrogen radical ofthe designated moiety is replaced with the radical of a specifiedsubstituent, provided that the substitution results in a stable orchemically feasible compound. The phrase “one or more substituents”, asused herein, refers to a number of substituents that equals from one tothe maximum number of substituents possible based on the number ofavailable bonding sites, provided that the above conditions of stabilityand chemical feasibility are met. Unless otherwise indicated, anoptionally substituted group may have a substituent at eachsubstitutable position of the group, and the substituents may be eitherthe same or different.

As used herein, the term “independently selected” means that the same ordifferent values may be selected for multiple instances of a givenvariable in a single compound. By way of example, in a compound offormula (I), if Ring A is substituted with two substituents —R^(2h),each substituent is selected from the group of defined values forR^(2h), and the two values selected may be the same or different.

An aryl (including the aryl moiety in aralkyl, aralkoxy, aryloxyalkyland the like) or heteroaryl (including the heteroaryl moiety inheteroaralkyl and heteroaralkoxy and the like) group may contain one ormore substituents. Examples of suitable substituents on the unsaturatedcarbon atom of an aryl or heteroaryl group include -halo, —NO₂, —CN,—R*, —C(R*)═C(R*)₂, —C≡C—R*, —OR*, —SR^(o), —S(O)R^(o), —SO₂R^(o),—SO₃R*, —SO₂N(R⁺)₂, —N(R⁺)₂, —NR⁺C(O)R*, —NR⁺C(O)N(R⁺)₂, —NR⁺CO₂R—,—O—CO₂R*, —OC(O)N(R⁺)₂, —O—C(O)R*, —CO₂R*, —C(O)—C(O)R*, —C(O)R*,—C(O)N(R⁺)₂, —C(O)N(R⁺)C(═NR⁺)—N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)—C(O)R*,—C(═NR⁺)—N(R⁺)₂, —C(═NR⁺)—OR*, —N(R⁺)—N(R⁺)₂, —N(R⁺)C(═NR⁺)—N(R⁺)₂,—NR⁺SO₂R^(O), —NR⁺SO₂N(R⁺)₂, —P(O)(R*)₂, —P(O)(OR*)₂, —O—P(O)—OR*, and—P(O)(NR⁺)—N(R⁺)₂, wherein R^(o) is an optionally substituted aliphaticor aryl group, and R⁺ and R* are as defined above, or two adjacentsubstituents, taken together with their intervening atoms, form a 5-6membered unsaturated or partially unsaturated ring having 0-3 ring atomsselected from the group consisting of N, O, and S.

An aliphatic group or a non-aromatic heterocyclic ring may besubstituted with one or more substituents. Examples of suitablesubstituents on the saturated carbon of an aliphatic group or of anon-aromatic heterocyclic ring include, without limitation, those listedabove for the unsaturated carbon of an aryl or heteroaryl group and thefollowing: ═O, ═S, ═C(R*)₂, ═N—N(R*)₂, ═N—OR*, ═N—NHC(O)R*,═N—NHCO₂R^(o), ═N—NHSO₂R^(o), or ═N—R*, where each R* and R^(o) is asdefined above.

Suitable substituents on the nitrogen atom of a non-aromaticheterocyclic ring include —R*, —N(R*)₂, —C(O)R*, —CO₂R*, —C(O)—C(O)R*,—C(O)CH₂C(O)R*, —SO₂R*, —SO₂N(R*)₂, —C(═S)N(R*)₂, —C(═NH)—N(R*)₂, and—NR*SO₂R*; wherein each R* is as defined above.

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 10%.

As used herein, the term “comprises” means “includes, but is not limitedto.”

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention. Unlessotherwise stated, structures depicted herein are also meant to includeall stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.When a mixture is enriched in one enantiomer relative to its opticalisomer, the mixture preferably contains an enantiomeric excess of atleast 50%, 75%, 90%, 95%, 99%, or 99.5%. Similarly, when a mixture isenriched in one diastereomer relative to other diastereomer(s), themixture preferably contains a diastereomeric excess of at least 50%,75%, 90%, 95%, 99%, or 99.5%.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructure except for the replacement of a hydrogen atom by a deuteriumor tritium, or the replacement of a carbon atom by a ¹³C- or¹⁴C-enriched carbon are within the scope of the invention.

Also included within the scope of the invention are solvates of thecompounds disclosed herein. As used herein, the term “solvate” means aphysical association of a compound of this invention with one or moresolvent molecules. This physical association includes hydrogen bonding.In certain instances, the solvate will be capable of isolation, forexample when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Representative solvates includehydrates, ethanolates, and methanolates.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio.

The present invention provides compounds of formula (I), as describedabove, and pharmaceutically acceptable salts thereof. In formula (I), Y¹is N or CH and Y² is N or CR^(e), provided that at least one of Y¹ andY² is N. The variable R^(e) is hydrogen, halo, —NO₂, —CN, —C(R⁵)═C(R⁵)₂,—C≡C—R⁵, —C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R¹⁰, —OR⁵, —N(R⁴)₂, —NR⁴C(O)R⁵,—NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —CO₂R⁵, —C(O)R⁵, —C(O)N(R⁴)₂, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, or an optionally substituted C₁₋₄ aliphatic.

One embodiment of the invention relates to a compound of formula (I),wherein Y² is CR^(e) and R^(e) is hydrogen, halo, C₁₋₄ aliphatic, C₁₋₄fluoroaliphatic, —R^(2e), -T³-R^(1e), -T³-R^(2e), —V²-T³-R^(1e), or—V²-T³-R^(2e). The variables V², T³, R^(1e), R^(2e) have the valuesdescribed below.

V² is —C(R⁵)═C(R⁵)— or —C≡C—.

T³ is a C₁₋₄alkylene chain optionally substituted with one or two R³. Insome embodiments, T³ is a C₁₋₃ alkylene chain.

R^(1e) is an optionally substituted aryl, heteroaryl, heterocyclyl, orcycloaliphatic ring.

R^(2e) is —NO₂, —CN, —C(R⁵)═C(R)₂, —C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R⁵, —C≡C—R¹⁰,—OR⁵, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —CO₂R⁵, —C(O)R⁵,—C(O)N(R⁴)₂, —N(R⁴)SO₂R⁶, or —N(R⁴)SO₂N(R⁴)₂. In some embodiments,R^(2e) is —OR⁵, —N(R⁴)₂, —CN, —CO₂R⁵, —C(O)N(R⁴)₂, —C(R⁵)═C(R⁵)₂,—C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R⁵, or —C≡C—R¹⁰.

In particular embodiments of the present invention, the compound offormula (I) is characterized by one or more, and preferably all, of thefollowing features (a)-(e):

(a) Y¹ is N;

(b) Y² is CR^(e), where R^(e) is selected from the group consisting ofhydrogen, C₁₋₄ aliphatic, Cl, fluoroaliphatic, -halo, —OR⁵, —N(R⁴)₂,—CN, —CO₂R⁵, —C(O)N(R⁴)₂, —C(R⁵)═C(R⁵)₂, —C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R⁵, and—C≡C—R¹⁰;

(c) G¹ is C═O;

(d) R^(c) is selected from the group consisting of hydrogen, fluoro,—OR⁵, —N(R⁴)₂, and C₁₋₄ aliphatic optionally substituted with one or twogroups independently selected from C₁₋₃ aliphatic, fluoro, —OR⁵,—N(R⁴)₂, —CO₂R⁵, —C(O)N(R⁴)₂, and optionally substituted 5- or6-membered aryl or heteroaryl; and

(e) R^(d) is hydrogen.

Some embodiments of the invention relate to a compound of formula (I),wherein Y¹ is N, Y² is CR^(e), G¹ is C═O, R^(c) is hydrogen or C₁₋₄aliphatic, and R^(d) is hydrogen. In a particular embodiment, Y¹ is N,Y² is CH, G¹ is C═O, and each of R^(c) and R^(d) is hydrogen.

Ring A is a substituted or unsubstituted 5- or 6-membered aryl orheteroaryl ring. Nonlimiting examples of Ring A include furano, thieno,pyrrolo, oxazolo, thiazolo, imidazolo, pyrazolo, isoxazolo, isothiazolo,oxadiazolo, triazolo, thiadiazolo, benzo, pyridino, pyridazino,pyrimidino, pyrazino, and triazino, any of which groups may besubstituted or unsubstituted. Particular values for Ring A includesubstituted or unsubstituted rings selected from the group consisting offurano, thieno, benzo, pyridino, pyridazino, pyrimidino, and pyrazino.

In some embodiments, Ring A is substituted with 0-2 R^(h) and 0-2R^(8h), or is substituted with 0-1 R^(h) and 0-2 R^(8h). Each R^(h)independently is selected from the group consisting of C₁₋₆ aliphatic,C₁₋₆ fluoroaliphatic, halo, —R^(1h), —R^(2h), -T⁴-R^(2h), -T⁴-R^(1h),—V³-T⁴, R^(1h), and —V³-T⁴-R^(2h), or two adjacent R^(h), taken togetherwith the intervening ring atoms, form an optionally substituted fused 5-to 6-membered aromatic or 4- to 8-membered non-aromatic ring having 0-3ring heteroatoms selected from the group consisting of O, N, and S. EachR^(8h) independently is selected from the group consisting of C₁₋₄aliphatic, C₁₋₄ fluoroaliphatic, -halo, and —O(C₁₋₄ aliphatic).

The variables R^(1h), R^(2h), T⁴, and V³ have the values describedbelow.

Each R^(1h) independently is an optionally substituted aryl, heteroaryl,heterocyclyl, or cycloaliphatic ring. In some embodiments, R^(1h) is anoptionally substituted 5- or 6-membered aryl, heteroaryl, heterocyclyl,or cycloaliphatic ring.

Each R^(2h) independently is —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵,—C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R¹⁰, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, SO₃R⁵,—SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —O—CO₂R⁵,—OC(O)N(R⁴)₂, —O—C(O)R⁵, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵, —C(O)N(R⁴)₂,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O), —C(═NR⁴)—N(R⁴)₂,—C(═NR⁴)—OR⁵, —C(R⁶)═N—OR⁵, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, —P(O)(R⁵)₂, or —P(O)(OR⁵)₂. In some embodiments, R^(2h)is —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —OR⁵, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂,—NR⁴CO₂R⁶, —OC(O)N(R⁴)₂, —C(O)R⁵, —C(O)N(R⁴)₂—N(R⁴)SO₂R⁶, or—N(R⁴)SO₂N(R⁴)₂. In certain embodiments, R^(2h) is —N(R⁴)₂, —C(O)R⁵, or—C(O)N(R⁴)₂.

V³ is —(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—,—N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—, —C(O)N(R⁴)—,—C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, —OC(O)N(R⁴)—, —C(NR⁴)═N—,—C(OR⁵)═N—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—, —P(O)R⁵)—, —P(O)(OR⁵)—O—,—P(O)—O—, or —P(O)(NR⁵)—N(R⁵)—. In some embodiments, V³ is—C(R⁵)═C(R⁵)—, —C≡C—, —O—, —N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—,—N(R⁴)CO₂—, —OC(O)N(R⁴)—, —C(O)—, —C(O)N(R⁴)—, —N(R⁴)SO₂—, or—N(R⁴)SO₂N(R⁴)—. In certain embodiments, V³ is —C(R⁵)—C(R⁵)—, —C≡C—, or—C(O)N(R⁴)—.

T⁴ is a C₁₋₆ alkylene chain optionally substituted with one or twoindependently selected R^(3a) or R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—,—S(O)₂—, —SO₂N(R⁴)—, —N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—,—C(O)N(R⁴)—, —C(O)—, —C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—,—OC(O)N(R⁴)—, —N(R⁴)SO₂—, or —SO₂N(R⁴)—, and wherein T⁴ or a portionthereof optionally forms part of a 3-7 membered ring. In someembodiments, T⁴ is a C₁₋₄ or C₂₋₄alkylene chain, optionally substitutedwith one or two independently selected R^(3a) or R^(3b).

Each R^(3a) independently is selected from the group consisting of —F,—OH, —O(C₁₋₃ alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₃ alkyl), —CO₂H,—CO₂(C₁₋₃alkyl), —C(O)NH₂, and —C(O)NH(C₁₋₃ alkyl). In some embodiments,R^(3a) is —F, —OH, —O(C₁₋₃ alkyl), or —N(R⁴)₂, where each R⁴independently is hydrogen, C₁₋₄alkyl, or C₆₋₁₀ar(C₁₋₆)alkyl, the arylportion of which is optionally substituted, or —N(R⁴)₂ is an optionallysubstituted pyrrolidinyl, imidazolyl, pyrazolyl, piperidinyl,morpholinyl, or piperazinyl ring.

Each R^(3b) independently is a C₁₋₃ aliphatic optionally substitutedwith R^(3a) or R⁷, or two substituents R^(3b) on the same carbon atom,taken together with the carbon atom to which they are attached, form a3- to 6-membered carbocyclic ring. Each R⁷ independently is anoptionally substituted aryl or heteroaryl ring.

In some embodiments, Ring A is an optionally substituted pyridino,thieno, or furano ring, wherein Ring A is substituted with 0, 1, or 2R^(h) and 0, 1, or 2 R^(h), where R^(h) and R^(8h) have the valuesdescribed above. In some such embodiments, two adjacent substituents onRing A are taken together to form an optionally substituted fused 5- to-6-membered aromatic or 4- to 8-membered non-aromatic ring having 0-3ring heteroatoms selected from the group consisting of O, N, and S. Incertain such embodiments, two adjacent substituents on Ring A are takentogether to form a fused benzene ring.

In some other embodiments, Ring A is an optionally substituted phenylring, and the invention relates to a compound of formula (II):

or a pharmaceutically acceptable salt thereof;

wherein Ring A is substituted with 0, 1, or 2 R^(h) and 0, 1, or 2R^(8h). The variables R^(a), R^(b), R^(c), R^(d), R^(h), R^(8h), G¹, Y¹,and Y² have the values described above for formula (I).

In certain embodiments, the compound of formula (II) is represented byone of formulae (II-A)-(II-F):

In some embodiments, Ring A in formula (II) is substituted with 0-2substituents independently selected from the group consisting of Cl,aliphatic, C₁₋₄ fluoroaliphatic, -halo, and —O(C₁₋₄ aliphatic), or twoadjacent substituents on Ring A, taken together with the interveningring atoms, form a fused dioxolane or dioxane ring.

In some embodiments, Ring A in formula (II) has the formula A-i, A-ii,or A-iii:

R^(h) and R^(8h) are as described above for formula (I), and m is 0, 1,or 2, preferably 0 or 1.

In some embodiments, R^(h) in formula A-i or A-ii is selected from —CN,—CO₂R⁵, —C(O)N(R⁴)₂, —N(R⁴)₂, or —OR⁵. In a particular embodiment, R^(h)is —C(O)N(R⁴)₂ or —N(R⁴)₂, wherein one R⁴ is hydrogen or C₁₋₄alkyl, andthe other R⁴ is hydrogen, C₁₋₄alkyl, or a phenyl, cyclohexyl,piperidinyl, piperazinyl, or pyrrolidinyl ring, any of which groupsoptionally is substituted with one or two substituents independentlyselected from the group consisting of -halo, C₁₋₄ aliphatic, C₁₋₄fluoroaliphatic, —OH, —O(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄alkyl), and—N(C₁₋₄alkyl)₂, or two adjacent substituents on a phenyl ring optionallyare taken together to form a fused furan, dihydrofuran, oxazole,pyrrole, dioxolane, or dioxane ring. In another particular embodiment,R^(h) is —C(O)N(R⁴)₂ or —N(R⁴)₂, wherein the two R⁴ are taken togetherwith the nitrogen to which they are attached to form a piperidinyl,piperazinyl, or pyrrolidinyl ring optionally substituted with one or twosubstituents independently selected from the group consisting of-fluoro, C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, —OH, —O(C₁₋₄alkyl), —NH₂,—NH(C₁₋₄alkyl), and —N(C₁₋₄alkyl)₂.

In other embodiments, R^(h) in formula A-i or A-ii is -T⁴-R^(2h),—V³-T⁴-R^(1h), or -Cy-T⁴-R^(2h), where Cy is a 5- or 6-membered aryleneor heteroarylene. In some such embodiments, T⁴ is a C₁₋₄alkylene chain;V³ is —C≡C—, —C(R⁵)═C(R⁵)—, —N(R⁴)—, or —C(O)N(R⁴)—; Cy is phenylene orthienylene; and R^(2h) is —OR⁵, —N(R⁴)₂, or —C(O)N(R⁴)₂. In a particularembodiment, R^(2h) is —N(R⁴)₂, wherein one R⁴ is hydrogen or C₁₋₄alkyl,and the other R⁴ is hydrogen, C₁₋₄alkyl, optionally substituted C₆₋₁₀aryl, or optionally substituted C₆₋₁₀ar(C₁₋₄)alkyl. In anotherparticular embodiment, R^(2h) is —N(R⁴)₂, wherein the two R⁴, takentogether with the nitrogen to which they are attached, form apiperidinyl, piperazinyl, or pyrrolidinyl ring optionally substitutedwith one or two substituents independently selected from the groupconsisting of -fluoro, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, —OH, —O(C₁₋₄alkyl), —NH₂, —NH(C₁₋₄ alkyl), and —N(C₁₋₄ alkyl)₂.

The variable R^(a) is hydrogen, —C(O)R^(5a), —C(O)N(R^(4a))₂,—CO₂R^(6a), —SO₂R^(6a), —SO₂N(R^(4a))₂, an optionally substituted C₁₋₁₀aliphatic, or an optionally substituted aryl, heteroaryl, orheterocyclyl ring. One embodiment of the invention relates to a compoundof formula (I), wherein R^(a) is hydrogen, C₁₋₆ aliphatic, or asubstituted C₁₋₆ aliphatic having the formula -T¹¹-R^(1a), -T¹¹-R^(21a),or -T¹²-R^(22a). In another embodiment, R^(a) is —V¹-T¹¹-R^(1a),—V¹-T¹¹-R^(21a), or —V¹-T¹¹-R^(22a). In another embodiment, R^(a) is—R^(1a) or -T¹¹-R^(1a). The variables V¹, T¹¹, T¹², R^(1a), R^(21a), andR^(22a) have the values described below.

V¹ is —C(O)—, —C(O)N(R^(4a))—, —C(O)O—, —SO₂—, or —SO₂N(R^(4a))—. Incertain embodiments, V¹ is —C(O)—.

T¹¹ is a C₁₋₆ alkylene chain optionally substituted with one or twoindependently selected R^(3a) or R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R⁵)═C(R⁵)— or —C≡C—. The variablesR^(3a) and R^(3b) have the values and preferred values described abovein connection with Ring A. In certain embodiments, T¹¹ is a C₁₋₃alkylene chain optionally substituted with one or two independentlyselected R^(3a) or R^(3b).

T¹² is a C₂₋₆ alkylene chain optionally substituted with one or twoindependently selected R^(3a) or R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R⁵)═C(R⁵)— or —C≡C—. In certainembodiments, T¹² is a C₂₋₃ alkylene chain optionally substituted withone or two independently selected R^(3a) or R^(3b).

R^(21a) is —C(R^(5a))⊚C(R^(5a))₂, C≡C—R^(5a), S(O)R^(6a), —SO₂R^(6a),—SO₃R^(6a), —SO₂N(R^(4a))₂, —CO₂R^(5a), C(O)—C(O)R^(5a), —C(O)R^(5a),—C(O)N(R^(4a))₂, —C(O)N(R^(4a))C(═NR^(4a))—N(R^(4a))²,C(═NR^(4a))—N(R^(4a))₂, C(═NR^(4a))—OR^(a), C(R^(6a))═N—OR^(5a),—P(O)(R^(5a))₂, or —P(O)(OR^(5a))₂. In certain embodiments, R^(21a) is—CO₂R^(5a), —C(O)N(R^(4a))₂, —SO₂N(R^(4a))₂,—C(O)N(R^(4a))C(═NR^(4a))—N(R^(4a))₂, or —C(═NR^(4a))—N(R^(4a))₂.

R^(22a) is —NO₂, —CN, —OR^(5a), —SR^(6a), —N(R^(4a))₂,—NR^(4a)C(O)R^(5a), —NR^(4a)C(O)N(R^(4a))₂, —NR^(4a)CO₂R^(6a),O—CO₂R^(5a), —OC(O)N(R^(4a))₂, —O—C(O)R^(5a),N(R^(4a))C(═NR^(4a))—N(R^(4a))₂, —N(R^(4a))C(═NR^(4a))—N(R^(4a))—C(O)R⁵,—N(R^(4a))SO₂R^(6a), or —N(R^(4a))SO₂N(R^(4a))₂. In certain embodiments,R^(22a) is —OR^(5a), —N(R^(4a))₂, —NR^(4a)C(O)R^(a),NR^(4a)C(O)N(R^(4a))₂, —N(R^(4a))C(═NR^(4a))N(R^(4a))₂,N(R^(4a))C(═NR^(4a))—N(R^(4a))—C(O)R⁵, or —N(R^(4a))SO₂R^(6a).

R^(1a) is an optionally substituted aryl, heteroaryl, heterocyclyl, orcycloaliphatic ring. In some embodiments, R^(1a) is a 5- or 6-memberedaryl or heteroaryl ring that is substituted with 0, 1, or 2independently selected R^(j) and 0, 1, or 2 independently selectedR^(8j). Each R^(j) independently is selected from the group consistingof C₁₋₆ aliphatic, C₁₋₆ fluoroaliphatic, halo, —R^(1j), —R^(2j),-T⁵-R^(2j), -T⁵-R^(1j), —V⁴-T⁵-R^(1j), and —V⁴-T⁵-R^(2j); or twoadjacent R^(j), taken together with the intervening ring atoms, form anoptionally substituted fused 5- to 6-membered aromatic or 4- to8-membered non-aromatic ring having 0-3 ring heteroatoms selected fromthe group consisting of O, N, and S. Each R^(8j) independently isselected from the group consisting of C₁₋₄ aliphatic, C₁₋₄fluoroaliphatic, -halo, —CO₂H, —CO₂(C₁₋₄ aliphatic), —OH, and —O(C₁₋₄aliphatic). In some embodiments, two adjacent R^(j), taken together withthe intervening ring atoms, form an optionally substituted fused furan,dihydrofuran, oxazole, pyrrole, dioxolane, or dioxane ring.

The variables R^(1j), R^(2j), T⁵, and V⁴ have the values describedbelow:

Each R^(1j) independently is an optionally substituted aryl, heteroaryl,heterocyclyl, or cycloaliphatic ring. In some embodiments, R^(1j) is anoptionally substituted 5- to 6-membered aryl, heteroaryl, heterocyclyl,or cycloaliphatic ring.

Each R² independently is —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵,—C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R¹⁰, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₃R⁵,—SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —O—CO₂R⁵,—OC(O)N(R⁴)₂, —O—C(O)R⁵, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵, —C(O)N(R⁴)₂,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O), —C(═NR⁴)—N(R⁴)₂,—C(═NR⁴)—OR⁵, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂,—P(O)(R⁵)₂, or —P(O)(OR⁵)₂. In some embodiments, R² is —C(R⁵)═C(R⁵)₂,—C≡C—R⁵, —OR⁵, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶,—OC(O)N(R⁴)₂, —C(O)R⁵, —C(O)N(R⁴)₂—N(R⁴)SO₂R⁶, or —N(R⁴)SO₂N(R⁴)₂.

V⁴ is —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—,—N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—, —C(O)N(R⁴)—, —C(O)—,—C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, —OC(O)N(R⁴)—, —C(NR⁴)═N—,—C(OR⁵)═N—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—, —P(O)(R⁵)—, —P(O)(OR⁵)—O—,—P(O)—O—, or —P(O)(NR⁵)—N(R⁵)—. In some embodiments, V⁴ is—C(R⁵)═C(R⁵)—, —C≡C—, —O—, —N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—,—N(R⁴)CO₂—, —OC(O)N(R⁴)—, —C(O)—, —C(O)N(R⁴)—, —N(R⁴)SO₂—, or—N(R⁴)SO₂N(R⁴)—. In certain embodiments, V⁴ is —C(R⁵)═C(R⁵)—, —C≡C—, or—C(O)N(R⁴)—.

T⁵ is a C₁₋₆ alkylene chain optionally substituted with one or twoindependently selected R^(3a) or R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—,—S(O)₂—, —SO₂N(R⁴)—, —N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—,—C(O)N(R⁴)—, —C(O)—, —C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—,—OC(O)N(R⁴)—, —N(R⁴)SO₂—, or —SO₂N(R⁴)—, and wherein T⁵ or a portionthereof optionally forms part of a 3-7 membered ring. In someembodiments, T⁵ is a C₁₋₄ or C₂₋₄alkylene chain, optionally substitutedwith one or two independently selected R³¹ or R^(3b). The variablesR^(3a) and R^(3b) have the values and preferred values described abovein connection with Ring A.

In some embodiments, R^(a) is an optionally substituted 5- or 6-memberedaryl or heteroaryl ring. In some such embodiments, R^(a) is selectedfrom the group consisting of imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, and triazinyl.

In certain other embodiments, Ring B is an optionally substituted phenylring, and the invention relates to a compound of formula (III):

or a pharmaceutically acceptable salt thereof;

wherein Ring B is substituted with 0, 1, or 2 R^(j) and 0, 1, or 2R^(8j). Ring A, and the variables R^(b), R^(c), R^(d), R^(j), R^(8j),G¹, Y¹, and Y² have the values described above for formula (I). In somesuch embodiments, Ring B is substituted with 0-2 R^(8j) and one R^(j).

In some embodiments, R^(j) is an optionally substituted aryl,heteroaryl, or heterocyclyl ring. In certain such embodiments, R^(j) isselected from the group consisting of imidazolyl, pyrrolyl, pyrazolyl,oxazolyl, thienyl, phenyl, pyridyl, pyrimidinyl, piperazinyl,piperidinyl, or morpholinyl.

In other embodiments, R^(j) is selected from the group consisting of—CO₂R⁵, —C(O)N(R⁴)₂, —SO₂N(R⁴)₂, —C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—(N(R⁴)₂,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, and —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵. In certainsuch embodiments, R^(j) is —CO₂H.

In some other embodiments, R^(j) has the formula -T⁵-R^(2j) or—V⁴-T⁵-R^(2j), wherein V⁴ is —C≡C— or —C(R⁵)═C(R⁵)—, and R^(2j) is —OR⁵or —N(R⁴)₂.

In still other embodiments, R^(j) has the formula —V⁴-T⁵-R² or—V⁴-T⁵-R^(1j), wherein V⁴ is —C(O)N(R⁴)— or —SO₂N(R⁴)— and T⁵ is aC₂₋₄alkylene chain, optionally substituted with —F or C₁₋₄ aliphatic.The variables R^(1j) and R^(2j) have the values described above forformula (I). In certain embodiments, R¹¹ is an optionally substituted 3-to 6-membered heterocyclyl or an optionally substituted 5- to 6-memberedheteroaryl. A particular value for R^(2j) is —N(R⁴)₂, where each R⁴independently is hydrogen or C₁₋₄ aliphatic, or —N(R⁴)₂ is an optionallysubstituted 3- to 6-membered heterocyclyl or an optionally substituted5- to 6-membered heteroaryl, having, in addition to the nitrogen, 0-2ring heteroatoms selected from N, O, and S.

In some embodiments, Ring B is substituted with one or two substituentsindependently selected from the group consisting of C₁₋₄ aliphatic, C₁₋₄fluoroaliphatic, -halo, —OR⁵, or —N(R⁴)₂, or two adjacent R^(j), takentogether with the intervening ring atoms, form an optionally substitutedfused benzene, pyridine, furan, dihydrofuran, oxazole, thiazole,oxadiazole, thiadiazole, pyrrole, pyrazole, dioxolane, or dioxane ring.

In yet other embodiments, Ring B is substituted with 0-2 substituentsindependently selected from the group consisting of Cl, aliphatic, C₁₋₄fluoroaliphatic, -halo, and —O(C₁₋₄ aliphatic), or two adjacentsubstituents, taken together with the intervening ring atoms, form afused dioxolane or dioxane ring.

In some embodiments, Ring B has the formula B-i, B-ii, or B-iii:

-   wherein n is 0, 1, or 2, preferably 0 or 1. R^(j) and R^(8j) have    the values and preferred values described above described above for    formulae (I) and (III).

The variable R^(b) is hydrogen or an optionally substituted aliphatic,aryl, heteroaryl, or heterocyclyl group. In some embodiments, theinvention relates to a compound of formula (I), wherein R^(b) ishydrogen or C₁₋₆ aliphatic. In certain such embodiments, R^(b) ishydrogen or methyl.

In some other embodiments, the invention relates to a compound offormula (I), wherein R^(b) is an optionally substituted C₁₋₆ aliphatic.In some such embodiments, R^(b) has the formula -T²¹-R^(1b),-T²¹R—R^(21b) or -T²²-R²². The variables R^(1b), R^(21b), R^(22b) T²¹,and T²² have the values described below:

R^(1b) is an optionally substituted aryl, heteroaryl, heterocyclyl, orcycloaliphatic ring. In some embodiments, R^(1b) is an optionallysubstituted pyrrolyl, imidazolyl, pyrazolyl, triazolyl, phenyl, pyridyl,pyrimidinyl, pyrazinyl, pyrrolidinyl, piperidinyl, piperazinyl, ormorpholinyl ring.

R^(21b) is —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R¹⁰, —S(O)R⁶,—SO₂R⁶, —SO₃R⁵, —SO₂N(R⁴)₂, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵, —C(O)N(R⁴)₂,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵, —C(R⁶)═N—OR⁵,—P(O)(R⁵)₂, or —P(O)(OR⁵)₂. In some embodiments, R^(21b) is —CO₂R⁵ or—C(O)N(R⁴)₂. In certain such embodiments, R⁵ is hydrogen, C₁₋₄alkyl, orC₆₋₁₀ar(C₁₋₄)alkyl, and each R⁴ independently is hydrogen, C₁₋₄alkyl, orC₆₋₁₀ar(C₁₋₄)alkyl, or two R⁴, taken together with the nitrogen atom towhich they are attached, form an optionally substituted 5- to 6-memberedheterocyclyl ring having, in addition to the nitrogen atom, 0-2 ringheteroatoms selected from N, O, and S.

R^(22b) is —NO₂, —CN, —OR⁵, —SR⁶, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂,—NR⁴CO₂R⁶, —O—CO₂R⁵, —OC(O)N(R⁴)₂, —O—C(O)R⁵, —N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵, —N(R⁴)SO₂R⁶, or —N(R⁴)SO₂N(R⁴)₂. In someembodiments, R^(22b) is —OR⁵ or —N(R⁴)₂. In certain such embodiments, R⁵is hydrogen, C₁₋₄alkyl, or C₆₋₁₀ar(C₁₋₄)alkyl, and each R⁴ independentlyis hydrogen, C₁₋₄alkyl, or C₆₋₁₀ar(C₁₋₄)alkyl, or two R⁴, taken togetherwith the nitrogen atom to which they are attached, form an optionallysubstituted 5- to 6-membered heterocyclyl ring having, in addition tothe nitrogen atom, 0-2 ring heteroatoms selected from N, O, and S.

T²¹ is a C₁₋₆ alkylene chain optionally substituted with one or two R³,wherein the alkylene chain optionally is interrupted by —C(R⁵)═C(R⁵)— or—C≡C—. In some embodiments, T²¹ is a C₁₋₄alkylene chain. T²² is aC₂₋₆alkylene chain optionally substituted with one or two R³, whereinthe alkylene chain optionally is interrupted by —C(R⁵)═C(R⁵)— or —C≡C—.In some embodiments, T²² is a C₂₋₄alkylene chain.

In other embodiments, the invention relates to a compound of formula(I), wherein R^(b) is an optionally substituted aryl, heteroaryl, orheterocyclyl ring. In some such embodiments, R^(b) is a 5- or 6-memberedaryl or heteroaryl ring that is substituted with 0-2 independentlyselected R^(k) and 0-2 independently selected R^(8k). Each R^(k)independently is selected from the group consisting of C₁₋₆ aliphatic,C₁₋₆ fluoroaliphatic, -halo, —R^(1k), —R^(2k), -T⁶-R^(2k), -T⁶-R^(1k),—V⁵-T⁶-R^(2k), and —V⁵-T⁶-R^(2k); or two adjacent R^(k), taken togetherwith the intervening ring atoms, form an optionally substituted fused 4-to 8-membered aromatic or non-aromatic ring having 0-3 ring heteroatomsselected from the group consisting of O, N, and S. Each R^(8k)independently is selected from the group consisting of C₁₋₄ aliphatic,C₁₋₄ fluoroaliphatic, -halo, and —O(C₁₋₄ aliphatic).

The variables R^(1k), R^(2k), T⁶, and V⁵ have the values describedbelow:

Each R^(1k) independently is an optionally substituted aryl, heteroaryl,heterocyclyl, or cycloaliphatic ring. In some embodiments, R^(1k) is anoptionally substituted 5- or 6-membered aryl, heteroaryl, heterocyclyl,or cycloaliphatic ring.

Each R^(2k) independently is —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵,—C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R¹⁰), —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₃R⁵,—SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —O—C₂R⁵,—OC(O)N(R⁴)₂, —O—C(O)R⁵, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵, —C(O)N(R⁴)₂,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O), —C(═NR⁴)—N(R⁴)₂,—C(═NR⁴)—OR⁵, —N(R⁴)C(═NR⁴)—N(R⁴), —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂,—P(O)(R⁵)₂, or —P(O)(OR⁵)₂.

V⁵ is —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—,—N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—, —C(O)N(R⁴)—, —C(O)—,—C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, —OC(O)N(R⁴)—, —C(NR⁴)═N—,—C(OR⁵)═N—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—, —P(O)(R⁵)—, —P(O)(OR⁵)—O—,—P(O)—O—, or —P(O)(NR⁵)—N(R⁵)—. In some embodiments, V⁵ is—C(R⁵)═C(R⁵)—, —C≡C—, —O—, —N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—,—N(R⁴)CO₂—, —OC(O)N(R⁴)—, —C(O)—, —C(O)N(R⁴)—, —N(R⁴)SO₂—, or—N(R⁴)SO₂N(R⁴)—. In certain embodiments, V⁵ is —C(R⁵)═C(R⁵)—, —C≡C—, or—C(O)N(R⁴)—.

T⁶ is a C₁₋₆ alkylene chain optionally substituted with one or twoindependently selected R^(3a) or R^(3b), wherein the alkylene chainoptionally is interrupted by —(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—,—S(O)₂—, —SO₂N(R⁴)—, —N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—,—C(O)N(R⁴)—, —C(O)—, —C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—,—OC(O)N(R⁴)—, —N(R⁴)SO₂—, or —SO₂N(R⁴)—, and wherein T⁶ or a portionthereof optionally forms part of a 3-7 membered ring. The variablesR^(3a) and R^(3b) have the values and preferred values described abovein connection with Ring A.

In a particular embodiment, R^(b) is an optionally substituted phenylring, and the invention relates to a compound of formula (IV):

or a pharmaceutically acceptable salt thereof;

wherein Ring C is substituted with 0, 1, or 2 R^(k) and 0, 1, or 2R^(8k). Ring A, and the variables R^(a), R^(c), R^(d), R^(k), R^(8k),G¹, Y¹, and Y² have the values described above for formula (I).

In some such embodiments, Ring C is substituted with 0-2 R^(8k) and oneR^(k). In some embodiments, Ring C is substituted with 1 or 2 R^(8k). Insome embodiments, Ring C is substituted with 0-2 substituentsindependently selected from the group consisting of C₁₋₄ aliphatic, C₁₋₄fluoroaliphatic, -halo, and —O(C₁₋₄ aliphatic).

In certain embodiments, Ring C has the formula v or vi:

wherein each R^(8k) independently is selected from the group consistingof C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, -halo, and —O(C₁₋₄ aliphatic).

In some embodiments, the invention relates to a subgenus of thecompounds of formula (I) represented by formula (V):

or a pharmaceutically acceptable salt thereof;

wherein Ring A is substituted with 0-2 R^(h) and 0-2 R^(8h), and Ring Bis substituted with 0-2 R^(j) and 0-2 R^(8j). The variables G¹, Y¹, Y²,R^(b), R^(c), R^(d), R^(h), R^(j), R^(8h), and R^(8j) have the valuesand preferred values described above for formulae (I)-(III).

In some embodiments, the invention relates to a compound of any one offormulae (II)-(V), characterized by one or more, and preferably all, ofthe following features (a)-(e):

(a) Y¹ is N;

(b) Y² is CR^(e), where R^(e) is selected from the group consisting ofhydrogen, C₁₋₄ aliphatic, C₁₋₄ fluoroaliphatic, -halo, —OR⁵, —N(R⁴)₂,—CN, —CO₂R⁵, —C(O)N(R⁴)₂, —C(R⁵)═C(R⁵)₂, —C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R⁵, and—C≡C—R¹⁰;

(c) G¹ is C═O;

(d) R^(c) is selected from the group consisting of hydrogen, fluoro,—OR⁵, —N(R⁴)₂, and C₁₋₄ aliphatic optionally substituted with one or twogroups independently selected from C₁₋₄ aliphatic, fluoro, —OR⁵,—N(R⁴)₂, —CO₂R⁵, —C(O)N(R⁴)₂, and optionally substituted 5- or6-membered aryl or heteroaryl; and

(e) R^(d) is hydrogen.

In some embodiments, the invention relates to a compound of any one offormulae (I)-(V) wherein G¹ is C═O, Y¹ is N, Y² is CH, and each of R^(c)and R^(d) is hydrogen.

In some embodiments, the invention relates to a subgenus of thecompounds of formula (I) represented by formula (VI) or (VIa):

or a pharmaceutically acceptable salt thereof;

wherein Ring A is substituted with 0-2 R^(h) and 0-2 R^(8h), and Ring Bis substituted with 0-2 R^(j) and 0-2 R^(8j). The variables G¹, Y¹, Y²,R^(b), R^(c), R^(d), R^(h), R^(j), R^(8h), and R^(8j) have the valuesand preferred values described above for formulae (I)-(III).

In some embodiments, the invention relates to a subgenus of thecompounds of formula (I) represented by formula (VII) or (VIIa):

or a pharmaceutically acceptable salt thereof;

wherein Ring A is substituted with 0-2 R^(h) and 0-2 R^(8h), Ring B issubstituted with 0-2 R^(j) and 0-2 R^(8j), and Ring C is substitutedwith 0-2 R^(k) and 0-2 R^(8k). The variables G¹, Y¹, Y², R^(b), R^(c),R^(d), R^(h), R^(j), R^(k), R^(8h), R^(8j), and R^(8k) have the valuesand preferred values described above for formulae (I)-(IV).

Subgenus definitions for Rings A, B, and C described for any one offormulae (I)-(VI), or exemplified in any specific compound(s) disclosedherein, apply also to the other formulae. Compounds embodying anycombination of the preferred values for the variables described hereinare considered to be within the scope of the present invention.

Specific examples of compounds of formula (I) are shown below in Table1.

TABLE 1 Protein Kinase Inhibitors

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

I-28

I-29

I-30

I-31

I-32

I-33

I-34

I-35

I-36

I-37

I-38

I-39

I-40

I-41

I-42

I-43

I-44

I-45

I-46

I-47

I-48

I-49

I-50

I-51

I-52

I-53

I-54

I-55

I-56

I-57

I-58

I-59

I-60

I-61

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-69

I-70

I-71

I-72

I-73

I-74

I-75

I-76

I-77

I-78

I-79

I-80

I-81

I-82

I-83

I-84

I-85

I-86

I-87

I-88

I-89

I-90

I-91

I-92

I-93

I-94

I-95

I-96

I-97

I-98

I-99

I-100

I-101

I-102

I-103

I-104

I-105

I-106

I-107

I-108

I-109

I-110

1-111

I-112

I-113

I-114

I-115

I-116

I-117

I-118

I-119

I-120

I-121

I-122

I-123

I-124

I-125

I-126

I-127

I-128

I-129

I-130

I-131

I-132

I-133

I-134

I-135

I-136

I-137

I-138

I-139

I-140

I-141

I-142

I-143

I-144

I-145

I-146

I-147

I-148

I-149

I-150

I-151

I-152

I-153

I-154

I-155

I-156

I-157

I-158

I-159

I-160

I-161

I-162

I-163

I-164

I-165

I-166

I-167

I-168

I-169

I-170

I-171

I-172

I-173

I-174

I-175

I-176

I-177

I-178

I-179

I-180

I-181

I-182

I-183

I-184

I-185

I-186

I-187

I-188

I-189

I-190

I-191

I-192

I-193

I-194

I-195

I-196

I-197

I-198

I-199

I-200

I-201

I-202

I-203

I-204

I-205

I-206

I-207

I-208

I-209

I-210

I-211

I-212

I-213

I-214

I-215

I-216

I-217

I-218

I-219

I-220

I-221

I-222

I-223

I-224

I-225

I-226

I-227

I-228

I-229

I-230

I-231

I-232

I-233

I-234

I-235

I-236

I-237

I-238

I-239

I-240

I-241

I-242

I-243

I-244

I-245

I-246

I-247

I-248

I-249

I-250

I-251

I-252

I-253

I-254

I-255

I-256

I-257

I-258

I-259

I-260

I-261

I-262

I-263

I-264

I-265

I-266

I-267

I-268

I-269

I-270

I-271

I-272

I-273

I-274

I-275

I-276

I-277

I-278

I-279

I-280

I-281

I-282

I-283

I-284

I-285

I-286

I-287

I-288

I-289

I-290

I-291

I-292

I-293

I-294

I-295

I-296

I-297

I-298

I-299

I-300

I-301

I-302

I-303

I-304

I-305

I-306

I-307

I-308

I-309

I-310

I-311

I-312

I-313

I-314

I-315

I-316

I-317

I-318

I-319

I-320

I-321

I-322

I-323

I-324

I-325

I-326

I-327

I-328

I-329

I-330

I-331

I-332

I-333

I-334

I-335

I-336

I-337

I-338

I-339

I-340

I-341

I-342

I-343

I-344

I-345

I-346

I-347

I-348

I-349

I-350

I-351

I-352

I-353

I-354

I-355

I-356

I-357

I-358

I-359

I-360

I-361

I-362

I-363

I-364

I-365

I-366

I-367

I-368

I-369

I-370

I-371

I-372

I-373

I-374

I-375

I-376

I-377

I-378

I-379

I-380

I-381

I-382

I-383

I-384

I-385

I-386

I-387

I-388

I-389

I-390

I-391

I-392

I-393

I-394

I-395

I-396

I-397

I-398

I-399

I-400

I-401

I-402

I-403

I-404

I-405

I-406

I-407

I-408

I-409

I-410

I-411

I-412

I-413

I-414

I-415

I-416

I-417

I-418

I-419

I-420

I-421

I-422

I-423

I-424

I-425

I-426

I-427

I-428

I-429

I-430

I-431

I-432

I-433

I-434

I-435

I-436

I-437

I-438

I-439

I-440

I-441

I-442

I-443

I-444

I-445

I-446

I-447

I-448

I-449

I-450

I-451

I-452

I-453

I-454

I-455

I-456

I-457

I-458

I-459

I-460

I-461

I-462

I-463

I-464

I-465

I-466

I-467

I-468

I-469

I-470

I-471

I-472

I-473

I-474

I-475

I-476

I-477

I-478

I-479

I-480

I-481

I-482

I-483

I-484

I-485

I-486

I-487

I-488

I-489

I-490

I-491

I-492

I-493

I-494

I-495

I-496

I-497

I-498

I-499

I-500

I-501

I-502

I-503

I-504

I-505

I-506

I-507

I-508

I-509

I-510

I-511

I-512

I-513

I-514

I-515

I-516

I-517

I-518

I-519

I-520

I-521

I-522

I-523

I-524

I-525

I-526

I-527

I-528

I-529

I-530

I-531

I-532

I-533

I-534

I-535

I-536

I-537

I-538

I-539

I-540

I-541

I-542

I-543

I-544

I-545

I-546

I-547

I-548

I-549

I-550

I-551

I-552

I-553

I-554

I-555

I-556

I-557

I-558

I-559

I-560

I-561

I-562

I-563

I-564

I-565

I-566

I-567

I-568

I-569

I-570

I-571

I-572

I-573

I-574

I-575

I-576

I-577

I-578

I-579

I-580

I-581

I-582

I-583

I-584

I-585

I-586

I-587

I-588

I-589

I-590

I-591

I-592

I-593

I-594

I-595

I-596

I-597

I-598

I-599

I-600

I-601

I-602

I-603

I-604

I-605

I-606

I-607

I-608

I-609

I-610

I-611

I-612

I-613

I-614

I-615

I-616

I-617

I-618

I-619

I-620

I-621

I-622

I-623

I-624

I-625

I-626

I-627

I-628

I-629

I-630

I-631

I-632

I-633

I-634

I-635

I-636

I-637

I-638

I-639

I-640

I-641

I-642

I-643

I-644

I-645

I-646

I-647

I-648

I-649

I-650

I-651

I-652

I-653

I-654

I-655

I-656

I-657

I-658

I-659

I-660

I-661

I-662

I-663

I-664

I-665

I-666

I-667

I-668

I-669

I-670

I-671

I-672

I-673

I-674

I-675

I-676

I-677

I-678

I-679

I-680

I-681

I-682

I-683

I-684

I-685

I-686

I-687

I-688

I-689

I-690

I-691

I-692

I-693

I-694

I-695

I-696

I-697

I-698

I-699

I-700

I-701

I-702

I-703

I-704

I-705

I-706

I-707

I-708

I-709

I-710

I-711

I-712

I-713

I-714

I-715

I-716

I-717

I-718

I-719

I-720

I-721

I-722

I-723

I-724

I-725

I-726

I-727

I-728

I-729

I-730

I-731

I-732

I-733

I-734

I-735

I-736

I-737

I-738

I-739

I-740

I-741

I-742

I-743

I-744

I-745

I-746

I-747

I-748

I-749

I-750

I-751

I-752

I-753

I-754

I-755

I-756

I-757

I-758

I-759

I-760

I-761

I-762

I-763

I-764

I-765

I-766

I-767

I-768

I-769

I-770

I-771

I-772

I-773

I-774

I-775

I-776

I-777

I-778

I-779

I-780

I-781

I-782

I-783

I-784

I-785

I-786

I-787

I-788

I-789

I-790

I-791

I-792

I-793

I-794

I-795

I-796

I-797

I-798

I-799

I-800

I-801

I-802

I-803

I-804

I-805

I-806

I-807

I-808

I-809

I-810

I-811

I-812

I-813

I-814

I-815

I-816

I-817

I-818

I-819

I-820

I-821

I-822

I-823

I-824

I-825

I-826

I-827

I-828

I-829

I-830

I-831

I-832

I-833

I-834

I-835

I-836

I-837

I-838

I-839

I-840

I-841

I-842

I-843

I-844

I-845

I-846

I-847

I-848

I-849

I-850

I-851

I-852

I-853

I-854

I-855

I-856

I-857

I-858

I-859

I-860

I-861

I-862

I-863

I-864

I-865

I-866

I-867

I-868

I-869

I-870

I-871

I-872

I-873

I-874

I-875

I-876

I-877

I-878

I-879

I-880

I-881

I-882

I-883

I-884

I-885

I-886

I-887

I-888

I-889

I-890

I-891

I-892

I-893

I-894

I-895

I-896

I-897

I-898

I-899

I-900

I-901

I-902

I-903

I-904

I-905

I-906

I-907

I-908

I-909

I-910

I-911

I-912

I-913

I-914

I-915

I-916

I-917

I-918

I-919

I-920

I-921

I-922

I-923

I-924

I-925

I-926

I-927

I-928

I-929

I-930

I-931

I-932

I-933

I-934

I-935

I-936

I-937

I-938

I-939

I-940

I-941

I-942

I-943

I-944

I-945

I-946

I-947

I-948

I-949

I-950

I-951

I-952

I-953

I-954

I-955

I-956

I-957

I-958

I-959

I-960

I-961

I-962

I-963

I-964

I-965

I-966

I-967

I-968

I-969

I-970

I-971

I-972

I-973

I-974

I-975

I-976

I-977

I-978

I-979

I-980

I-981

I-982

I-983

I-984

I-985

I-986

I-987

I-988

I-989

I-990

I-991

I-992

I-993

I-994

I-995

I-996

I-997

I-998

I-999

I-1000

I-1001

I-1002

I-1003

I-1004

I-1005

I-1006

I-1007

I-1008

I-1009

I-1010

I-1011

I-1012

I-1013

I-1014

I-1015

I-1016

I-1017

I-1018

I-1019

I-1020

I-1021

I-1022

I-1023

I-1024

I-1025

I-1026

I-1027

I-1028

I-1029

I-1030

I-1031

I-1032

I-1033

I-1034

I-1035

I-1036

I-1037

I-1038

I-1039

I-1040

I-1041

I-1042

I-1043

I-1044

I-1045

I-1046

I-1047

I-1048

I-1049

I-1050

I-1051

I-1052

I-1053

I-1054

I-1055

I-1056

I-1057

I-1058

I-1059

I-1060

I-1061

I-1062

I-1063

I-1064

I-1065

I-1066

I-1067

I-1068

I-1069

I-1070

I-1071

I-1072

I-1073

I-1074

I-1075

I-1076

I-1077

I-1078

I-1079

I-1080

I-1081

I-1082

I-1083

I-1084

I-1085

I-1086

I-1087

I-1088

I-1089

I-1090

I-1091

I-1092

I-1093

I-1094

I-1095

I-1096

I-1097

I-1098

I-1099

I-1100

I-1101

I-1102

I-1103

I-1104

I-1105

I-1106

I-1107

I-1108

I-1109

I-1110

I-1111

I-1112

I-1113

I-1114

I-1115

I-1116

I-1117

I-1118

I-1119

I-1120

I-1121

I-1122

I-1123

I-1124

I-1125

I-1126

I-1127

I-1128

I-1129

I-1130

I-1131

I-1132

I-1133

I-1134

I-1135

I-1136

I-1137

I-1138

I-1139

I-1140

I-1141

I-1142

I-1143

I-1144

I-1145

I-1146

I-1147

I-1148

I-1149

I-1150

I-1151

I-1152

I-1153

I-1154

I-1155

I-1156

I-1157

I-1158

I-1159

I-1160

I-1161

I-1162

I-1163

I-1164

I-1165

I-1166

I-1167

I-1168

I-1169

I-1170

I-1171

I-1172

I-1173

I-1174

I-1175

I-1176

I-1177

I-1178

I-1179

I-1180

I-1181

I-1182

I-1183

I-1184

I-1185

I-1186

I-1187

I-1188

I-1189

I-1190

I-1191

I-1192

I-1193

I-1194

I-1195

I-1196

I-1197

I-1198

I-1199

I-1200

I-1201

I-1202

I-1203

I-1204

I-1205

I-1206

I-1207

I-1208

I-1209

I-1210

I-1211

I-1212

I-1213

I-1214

I-1215

I-1216

I-1217

I-1218

I-1219

I-1220

I-1221

I-1222

I-1223

I-1224

I-1225

I-1226

I-1227

I-1228

I-1229

I-1230

I-1231

I-1232

I-1233

I-1234

I-1235

I-1236

I-1237

I-1238

I-1239

I-1240

I-1241

I-1242

I-1243

I-1244

I-1245

I-1246

I-1247

I-1248

I-1249

I-1250

I-1251

I-1252

I-1253

I-1254

I-1255

I-1256

I-1257

I-1258

I-1259

I-1260

I-1261

I-1262

I-1263

I-1264

I-1265

I-1266

I-1267

I-1268

I-1269

I-1270

I-1271

I-1272

I-1273

I-1274

I-1275

I-1276

I-1277

I-1278

I-1279

The compounds in Table 1 above also may be identified by the followingchemical names:

Chemical Name

-   I-1    2-(3,4-Dimethoxy-phenylamino)-5,7-dihydro-1,3,7,8-tetraaza-dibenzo[a,c]cyclohepten-6-one-   I-2    9-Chloro-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-3    4-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoic    acid-   I-4    4-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoic    acid methyl ester-   I-5    4-(10-Fluoro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoic    acid-   I-6    4-(7-Benzyl-9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoic    acid-   I-7    4-(9-Chloro-7-methyl-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoic    acid-   I-8    4-(10-Methoxy-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoic    acid-   I-9    4-(9-Methyl-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoic    acid-   I-10    4-(9-Chloro-6-oxo-7-phenyl-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoic    acid-   I-11    9-Chloro-2-(4-chloro-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-12    9-Chloro-2-(2-chloro-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-13    9-Chloro-2-(3-chloro-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-14    9-Chloro-2-(4-methoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-15    9-Chloro-2-(3-methoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-16    9-Chloro-2-(2-methoxy-phenylamino)-5H,7H-benzolpyrimido[4,5-d]azepin-6-one-   I-17    9-Chloro-2-(3,4-dimethoxy-benzylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-18    10-Bromo-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-19    4-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-butyric    acid-   I-20    9-Chloro-2-methylamino-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-21    N′-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-yl)-N,N-dimethyl-guanidine-   I-22    9-Chloro-2-dimethylamino-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-23 2-Amino-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-24    10-Chloro-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-25    4-(10-Bromo-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoic    acid-   I-26    2-(3,4-Dimethoxy-phenylamino)-10-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-27    2-(3,4-Dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-28    9-Chloro-2-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-29    9-Chloro-2-(3,4-dimethyl-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-30    2-(3,4-Dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-31    2-(3,4-Dimethoxy-phenylamino)-10-(3-pyrrolidin-1-yl-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-32    2-(3,4-Dimethoxy-phenylamino)-9-(3-pyrrolidin-1-yl-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-33    2-(3,4-Dimethoxy-phenylamino)-9-ethynyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-34    2-(Benzo[1,3]dioxol-5-ylamino)-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-35    9-Chloro-2-(3,5-dimethyl-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-36    9-Chloro-2-(4-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-37    2-(3,4-Dimethoxy-phenylamino)-9-ethyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-38    9-(3-Amino-prop-1-ynyl)-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-39    {3-[2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-9-yl]-prop-2-ynyl}-carbamic    acid tert-butyl ester-   I-40    7-(3-Amino-propyl)-9-chloro-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-41    {3-[2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-9-yl]-propyl}-carbamic    acid tert-butyl ester-   I-42    2-(3,4-Dimethoxy-phenylamino)-9-methyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-43    2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylic    acid-   I-44 2-Amino-10-bromo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-45    9-Chloro-2-(4-ethynyl-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-46    2-[4-(3-Amino-prop-1-ynyl)-phenylamino]-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-47    9-Chloro-2-[4-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenylamino]-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-48    2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylic    acid (2-pyridin-4-yl-ethyl)-amide-   I-49    2-(3,4-Dimethoxy-phenylamino)-9-(3-pyrrolidin-1-yl-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-50    9-(3-Amino-propyl)-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-51 2-Amino-10-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-52    2-(3,4-Dimethoxy-phenylamino)-9-(3-hydroxy-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-53    2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylic    acid-   I-54    9-Chloro-2-[4-(3-hydroxy-prop-1-ynyl)-phenylamino]-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-55    9-Chloro-2-(3,5-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-56    2-(3,4-Dimethoxy-phenylamino)-10-(3-pyrrolidin-1-yl-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-57    2-[4-(3-Amino-propyl)-phenylamino]-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-58    9-Chloro-2-(3-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-59    10-(3-Amino-prop-1-ynyl)-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-60    10-(3-Amino-propyl)-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-61    9-Chloro-2-phenylamino-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-62    N-(2-Amino-ethyl)-3-(9-chloro-6-oxo-6,7-dihydro-5H-benzolpyrimido[4,5-d]azepin-2-ylamino)-benzamide-   I-63    N-(3-Amino-propyl)-3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzamide-   I-64    N-(4-Amino-butyl)-3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzamide-   I-65    9-Chloro-2-(3-hydroxy-4-methoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-66    9-Chloro-2-[4-(3-pyrrolidin-1-yl-propyl)-phenylamino]-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-67    2-[3-(3-Amino-prop-1-ynyl)-phenylamino]-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-68    4-(9-Chloro-5,7-dimethyl-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoic    acid-   I-69    4-(9-Chloro-5-methyl-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoic    acid-   I-70    2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylic    acid amide-   I-71    2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylic    acid (2-amino-ethyl)-amide-   I-72    2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylic    acid (3-amino-propyl)-amide-   I-73    2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylic    acid (4-amino-butyl)-amide-   I-74    10-(4-Amino-piperidine-1-carbonyl)-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-75    2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylic    acid (2-pyrrolidin-1-yl-ethyl)-amide-   I-76    2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylic    acid (3-amino-propyl)-amide-   I-77    2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylic    acid (3-pyrrolidin-1-yl-propyl)-amide-   I-78    [3-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-phenyl]-acetonitrile-   I-79    9-Chloro-2-(3-hydroxymethyl-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-80    9-Chloro-2-[3-(2-hydroxy-ethyl)-phenylamino]-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-81    2-(3,4-Dimethoxy-phenylamino)-9-(3-hydroxy-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-82    2-(3,4-Dimethoxy-phenylamino)-9-propyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-83    N-(10-Iodo-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-yl)-benzamide-   I-84    2-Amino-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylic    acid-   I-85    10-Bromo-2-(methyl-phenyl-amino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-86    2-[3-(2-Amino-ethyl)-phenylamino]-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-87    2-(3,4-Dimethoxy-phenylamino)-9-(3-methylamino-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-88    2-(3,4-Dimethoxy-phenylamino)-9-(3-dimethylamino-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-89    9-Chloro-2-[3-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenylamino]-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-90    3-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzonitrile-   I-91    2-(3,4-Dimethoxy-phenylamino)-9-(3-dimethylamino-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-92    2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carbonitrile-   I-93    3-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-N-(3-dimethylamino-propyl)-N-methyl-benzamide-   I-94    4-[9-Chloro-7-(2-fluoro-phenyl)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino]-benzoic    acid-   I-95    4-[9-Chloro-7-(2-fluoro-phenyl)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino]-N-methyl-N-(1-methyl-pyrrolidin-3-yl)-benzamide-   I-96    9-Chloro-7-(2,6-difluoro-phenyl)-2-[4-(4-methyl-piperazine-1-carbonyl)-phenylamino]-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-97    4-[9-Chloro-7-(2-fluoro-phenyl)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino]-benzenesulfonic    acid-   I-98    9-Chloro-2-(3,4-dimethoxy-phenylamino)-7-(2-fluoro-phenyl)-5,7-dihydro-3,4,7-triaza-dibenzo[a,c]cyclohepten-6-one-   I-99    9-Chloro-2-(3,4-dimethoxy-phenylamino)-7-(2-fluoro-phenyl)-5,7-dihydro-1,3,4,7-tetraaza-dibenzo[a,c]cyclohepten-6-one-   I-100    N-(3-Amino-propyl)-6-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-nicotinamide-   I-101    9-Chloro-2-[6-(3-pyrrolidin-1-yl-prop-1-ynyl)-pyridin-2-ylamino]-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-102    2-(Benzofuran-6-ylamino)-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-103    9-Chloro-2-(5-methyl-pyrazin-2-ylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-104    2-(4-Furan-3-yl-phenylamino)-9-(3-pyrrolidin-1-yl-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-105    2-(3-Aminomethyl-phenylamino)-10-(3-dimethylamino-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-106    9-(3-Dimethylamino-propyl)-2-(3-hydroxymethyl-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-107    9-Chloro-2-(pyridin-2-ylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-108    9-Chloro-2-(pyridin-3-ylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-109    9-Chloro-2-(pyridin-4-ylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-110    10-(3-Dimethylamino-propyl)-2-(pyridin-4-ylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-111    2-(Pyridin-3-ylamino)-9-(3-pyrrolidin-1-yl-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-112    5-Amino-9-chloro-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-113    10-(3-Diethylamino-propyl)-2-(4-methoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-114    2-(3,4-Dimethoxy-phenylamino)-9-(3-piperidin-1-yl-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-115    9-(3-Diethylamino-propyl)-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-116    2-(4-Methoxy-phenylamino)-10-(3-piperidin-1-yl-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-117    2-(3,4-Dimethoxy-phenylamino)-9-(3-morpholin-4-yl-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-118    2-(4-Methoxy-phenylamino)-10-(3-morpholin-4-yl-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-119    9-Chloro-2-[2-(3,5-difluoro-phenyl)-ethylamino]-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-120    9-Chloro-2-(4-trifluoromethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-121    9-Chloro-2-(3-trifluoromethyl-benzylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-122    2-(3-Methoxy-4-methyl-phenylamino)-9-trifluoromethyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-123    2-(3,4-Dimethoxy-phenylamino)-9-(1H-imidazol-2-yl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-124    9-Chloro-2-[4-(1H-imidazol-2-yl)-phenylamino]-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-125    2-[4-(1H-Pyrazol-4-yl)-phenylamino]-9-(3-pyrrolidin-1-yl-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-126    10-(1H-Imidazol-2-yl)-2-(4-methoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-127    9-Chloro-2-[3-(1H-imidazol-2-yl)-phenylamino]-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-128    2-[3-(1H-Imidazol-2-yl)-phenylamino]-9-(3-pyrrolidin-1-yl-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-129    2-[3-(3-Dimethylamino-propyl)-phenylamino]-9-thiophen-3-yl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-130    9-Amino-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-131    9-(3-Pyrrolidin-1-yl-propyl)-2-(3-thiophen-2-yl-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-132    2-(3,4-Dimethoxy-phenylamino)-9-dimethylamino-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-133    2-[3-(3-Diethylamino-propyl)-phenylamino]-9-methoxy-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-134    2-[3-(3-Dimethylamino-propyl)-phenylamino]-9-(1H-imidazol-2-yl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-135    2-(4-Methoxy-phenylamino)-10-(3-pyrrolidin-1-yl-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-136    2-(4-Methoxy-phenylamino)-10-(3-pyrrolidin-1-yl-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-137    7-(3-Amino-propyl)-9-chloro-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one-   I-138    9-Aminomethyl-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]-pyrimido[4,5-d]azepin-6-one-   I-139    2-[3-(3-Amino-propyl)-phenylamino]-9-chloro-5H,7H-benzo[b]pyrimido-[4,5-d]azepin-6-one-   I-140    2-(3-Aminomethyl-phenylamino)-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]-azepin-6-one-   I-141    N-(8-Chloro-2-oxo-4-vinyl-2,3-dihydro-1H-benzo[b]azepin-5-yl)-N′-(3-nitro-phenyl)-acetamidine-   I-142    2-[(4-methoxyphenyl)amino]-10-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-143    2-[(4-methoxyphenyl)amino]-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-144    2-[(3-aminophenyl)amino]-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-145    9-chloro-2-{[3-(3-hydroxypropyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-146    (2E)-3-{2-[(3,4-dimethoxyphenyl)amino]-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-9-yl}acrylamide-   I-147 tert-butyl    4-({9-chloro-2-[(3,4-dimethoxyphenyl)amino]-6-oxo-5,6-dihydro-7H-pyrimido[5,4-d][1]benzazepin-7-yl}methyl)piperidine-1-carboxylate-   I-148    2-(2-(2-[(3,4-dimethoxyphenyl)amino]-6-oxo-5,6-dihydro-7H-pyrimido[5,4-d][1]benzazepin-7-yl)ethyl)-1H-isoindole-1,3(2H)-dione-   I-149    9-chloro-2-[(3,4-dimethoxyphenyl)amino]-7-(piperidin-4-ylmethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-150    2-[(4-methoxyphenyl)amino]-9-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-151    2-[(3-methoxyphenyl)amino]-9-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-152    2-[(4-chlorophenyl)amino]-9-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-153    2-[(3-chlorophenyl)amino]-9-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-154    2-[(3,4-dimethylphenyl)amino]-9-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-155    9-chloro-2-({3-[3-(dimethylamino)propyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-156    9-chloro-2-({3-[3-(diethylamino)propyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-157    9-chloro-2-{[3-(3-morpholin-4-ylpropyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-158    9-chloro-2-{[3-(3-piperidin-1-ylpropyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-159    9-chloro-2-{[3-(3-pyrrolidin-1-ylpropyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-160    10-bromo-2-[(3-methoxyphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-161    10-bromo-2-[(3,5-dimethoxyphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-162    9-chloro-2-{[2-(4-methoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-163    9-chloro-2-[(4-methyl-1,3-thiazol-2-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-164    2-[(3-methoxyphenyl)amino]-10-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-165    2-[(3,4-dimethoxyphenyl)amino]-9-fluoro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-166    2-[(3-methoxyphenyl)amino]-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-167    2-[(3,5-dimethoxyphenyl)amino]-10-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-168    2-[(3,5-dimethoxyphenyl)amino]-O-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-169    9-chloro-2-({3-[4-(dimethylamino)but-1-yn-1-yl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-170    9-chloro-2-({3-[4-(dimethylamino)butyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-171    3-{[6-oxo-10-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl]amino}benzoic    acid-   I-172    9-chloro-7-[2-(diethylamino)ethyl]-2-[(3,4-dimethoxyphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-173    9-chloro-2-[(3,4-dimethoxyphenyl)amino]-7-(2-morpholin-4-ylethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-174    9-chloro-2-[(3,4-dimethoxyphenyl)amino]-7-[2-(1-methylpyrrolidin-2-yl)ethyl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-175    9-chloro-2-[(6-chloro-1,3-benzothiazol-2-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-176    3-{[6-oxo-10-(3-pyrrolidin-1-ylpropyl)-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl]amino}benzoic    acid-   I-177    2-anilino-10-iodo-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-178    2-(1,3-benzodioxol-5-ylamino)-10-iodo-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-179    9-chloro-2-[(6-methoxypyridin-3-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-180    9-chloro-2-[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-181    2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-182    9-chloro-2-{[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-183    9-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-2-{[4-(2-thienyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-184    2-anilino-10-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-185    2-(1,3-benzodioxol-5-ylamino)-10-(3-pyrrolidin-1-ylprop-1-yn-1-yl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-186    9-(3-pyrrolidin-1-ylpropyl)-2-{[4-(2-thienyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-187    9-chloro-2-{[4-(trifluoromethoxy)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-188    9-chloro-2-[(4-morpholin-4-ylphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-189    9-chloro-2-{[4-(dimethylamino)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-190    9-chloro-2-[(1-methyl-3-phenyl-1H-pyrazol-5-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-191    9-chloro-2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-192    9-chloro-2-[(5-methyl-1,3-thiazol-2-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-193    9-chloro-2-(1,3-dihydro-2-benzofuran-5-ylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-194    3-{3-[(10-iodo-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}propanoic    acid-   I-195    2-[(3-aminophenyl)amino]-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-196    2-[(4-aminophenyl)amino]-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-197    9-chloro-2-(pyridin-2-ylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-198    2-[(3,4-dimethoxyphenyl)amino]-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-199    2-[(4-methoxyphenyl)amino]-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-200    2-[(4-methylphenyl)amino]-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-201    2-amino-9-[(4-methoxyphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-202    2-[(3,4-dichlorophenyl)amino]-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-203    2-amino-9-(1,3-benzodioxol-5-ylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-204    2-[(4-chlorophenyl)amino]-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-205    2-amino-9-[(4-methylphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-206    2-amino-9-[(3-fluorophenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-207    2-{[4-(trifluoromethyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-208    2-[(3-fluorophenyl)amino]-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-209    4-[(6-oxo-6,7-dihydro-5H-pyrimido[4,5-d]thieno[3,2-b]azepin-2-yl)amino]benzoic    acid-   I-210    2-amino-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-211    2-anilino-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-212    2-[(4-iodophenyl)amino]-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-213    2-amino-7-[3-(dimethylamino)propyl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-214    2-amino-7-(2-methoxyethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-215 methyl    3-(2-amino-6-oxo-5,6-dihydro-7H-pyrimido[5,4-d][1]benzazepin-7-yl)propanoate-   I-216    2-amino-7-[3-(1H-pyrrol-1-yl)propyl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-217    2-amino-7-[2-(1-methylpyrrolidin-2-yl)ethyl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-218    2-amino-7-(2-morpholin-4-ylethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-219    2-anilino-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-220    2-(1,3-benzodioxol-5-ylamino)-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-221    2-[(3,4-dimethoxyphenyl)amino]-9-[5-(pyrrolidin-1-ylmethyl)-2-thienyl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-222    2-[(4-chlorophenyl)amino]-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-223    2-[(3-iodophenyl)amino]-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-224 tert-butyl    4-({2-[(3,4-dimethoxyphenyl)amino]-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-9-yl}carbonyl)piperazine-1-carboxylate-   I-225    2-amino-9-[(3-methoxyphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-226    2-{[3-(hydroxymethyl)phenyl]amino}-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-227    2-[(3,4-dimethoxyphenyl)amino]-6-oxo-N-(2-pyrrolidin-1-ylethyl)-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine-9-carboxamide-   I-228    2-[(3,4-dimethoxyphenyl)amino]-9-(piperazin-1-ylcarbonyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-229 tert-butyl    4-[({2-[(3,4-dimethoxyphenyl)amino]-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-9-yl}carbonyl)amino]piperidine-1-carboxylate-   I-230    2-amino-7-benzyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-231 2-amino-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-232    2-[(3,5-dimethoxyphenyl)amino]-9-iodo-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-233    2-amino-7-[3-(diethylamino)propyl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-234 tert-butyl    4-[(2-amino-6-oxo-5,6-dihydro-7H-pyrimido[5,4-d][1]benzazepin-7-yl)methyl]piperidine-1-carboxylate-   I-235    9-chloro-2-{[2-(3-fluorophenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-236    9-chloro-2-{[2-(1H-imidazol-5-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-237    9-chloro-2-{[2-(4-nitrophenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-238    2-{[2-(4-bromophenyl)ethyl]amino}-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-239    2-[(3-aminophenyl)amino]-10-ethyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-240    2-amino-9-{[4-(dimethylamino)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-241    2-[(3,4-dimethoxyphenyl)amino]-6-oxo-N-(3-pyrrolidin-1-ylpropyl)-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine-9-carboxamide-   I-242 tert-butyl    {trans-4-[({2-[(3,4-dimethoxyphenyl)amino]-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-9-yl}carbonyl)amino]cyclohexyl}carbamate-   I-243    2-[(4-ethynylphenyl)amino]-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-244    2-[(3,4-dimethoxyphenyl)amino]-6-oxo-N-piperidin-4-yl-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine-9-carboxamide-   I-245    N-(trans-4-aminocyclohexyl)-2-[(3,4-dimethoxyphenyl)amino]-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepine-9-carboxamide-   I-246    2-amino-7-(4-fluorobenzyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-247    2-[(3,4-dimethoxyphenyl)amino]-9-(2-pyrrolidin-1-ylethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-248    2-amino-7-(3-fluorobenzyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-249    2-amino-7-(4-methoxybenzyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-250    2-[(3-ethynylphenyl)amino]-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-251    2-amino-7-(4-methylbenzyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-252    2-amino-7-(4-chlorobenzyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-253    2-amino-7-(3,4-dichlorobenzyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-254    2-[(3,4-dimethoxyphenyl)amino]-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-255    2-amino-9-anilino-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-256    2-[(4-methoxyphenyl)amino]-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-257    2-amino-9-{[4-(trifluoromethyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-258    2-[(4-methylphenyl)amino]-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-259    2-[(3,4-dichlorophenyl)amino]-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-260    2-[(4-chlorophenyl)amino]-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-261    2-{[4-(trifluoromethyl)phenyl]amino}-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-262    2-[(3-fluorophenyl)amino]-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-263    4-[(6-oxo-6,7-dihydro-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-2-yl)amino]benzoic    acid-   I-264 2-amino-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-265 2-anilino-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-266    9-chloro-2-{[3-(trifluoromethoxy)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-267    9-chloro-2-[(5-chloropyridin-2-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-268    9-chloro-2-[(4-nitrophenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-269    9-chloro-2-(pyrimidin-4-ylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-270    9-chloro-2-(cyclopropylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-271    9-chloro-2-{[1-(hydroxymethyl)-2-methylpropyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-272    9-chloro-2-({4-[(3-methylpiperazin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-273    9-chloro-2-({4-[(3,5-dimethylpiperazin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-274    9-chloro-2-[(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-275    2-[(3,4-dimethoxyphenyl)amino]-7-methyl-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-276    2-[(3,4-dimethoxyphenyl)amino]-5,7-dihydro-6H-[l]benzofuro[3,2-b]pyrimido[4,5-d]azepin-6-one-   I-277    2-[(4-methoxyphenyl)amino]-5,7-dihydro-6H-[1]benzofuro[3,2-b]pyrimido[4,5-d]azepin-6-one-   I-278    2-[(4-methylphenyl)amino]-5,7-dihydro-6H-[1]benzofuro[3,2-b]pyrimido[4,5-d]azepin-6-one-   I-279    2-[(3,4-dichlorophenyl)amino]-5,7-dihydro-6H-[1]benzofuro[3,2-b]pyrimido[4,5-d]azepin-6-one-   I-280    2-[(4-chlorophenyl)amino]-5,7-dihydro-6H-[1]benzofuro[3,2-b]pyrimido[4,5-d]azepin-6-one-   I-281    2-{[4-(trifluoromethyl)phenyl]amino}-5,7-dihydro-6H-[1]benzofuro[3,2-b]pyrimido[4,5-d]azepin-6-one-   I-282    4-[(6-oxo-6,7-dihydro-5H-[1]benzofuro[3,2-b]pyrimido[4,5-d]azepin-2-yl)amino]benzoic    acid-   I-283    2-amino-5,7-dihydro-6H-[l]benzofuro[3,2-b]pyrimido[4,5-d]azepin-6-one-   I-284    2-{[3-(3-piperidin-1-ylpropyl)phenyl]amino}-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-285    2-amino-7-[4-(1H-pyrazol-1-yl)benzyl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-286    2-amino-7-[4-(1H-1,2,4-triazol-1-yl)benzyl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-287    2-amino-7-[(1-methyl-1H-1,2,3-benzotriazol-6-yl)methyl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-288    2-amino-7-[2-(diethylamino)ethyl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-289 methyl    4-(2-amino-6-oxo-5,6-dihydro-7H-pyrimido[5,4-d][1]benzazepin-7-yl)butanoate-   I-290    2-amino-7-(3-methoxypropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-291    2-amino-7-(piperidin-4-ylmethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-292    5-amino-2-[(3,4-dimethoxyphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-293    2-[(3-fluorophenyl)amino]-5,7-dihydro-6H-[1]benzofuro[3,2-b]pyrimido[4,5-d]azepin-6-one-   I-294    2-anilino-5,7-dihydro-6H-[1]benzofuro[3,2-b]pyrimido[4,5-d]azepin-6-one-   I-295    N-(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)benzamide-   I-296    2-methoxy-N-(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)benzamide-   I-297    4-chloro-N-(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)benzamide-   I-298    3,4-dichloro-N-(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)benzamide-   I-299    3,4-dimethoxy-N-(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)benzamide-   I-300    2-({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl)amino}-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-301    N-[2-(dimethylamino)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[4,5-d]thieno[3,2-b]azepin-2-yl)amino]benzamide-   I-302 tert-butyl    (1-{4-[(6-oxo-6,7-dihydro-5H-pyrimido[4,5-d]thieno[3,2-b]azepin-2-yl)amino]benzoyl}pyrrolidin-3-yl)carbamate-   I-303    2-[(4-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-304    2-({4-[(3-methylpiperazin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-305    2-[(2-methoxyphenyl)amino]-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-306    2-[(2-fluorophenyl)amino]-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-307    2-[(2-methylphenyl)amino]-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-308    2-[(2-methoxyphenyl)amino]-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-309    2-[(2-fluorophenyl)amino]-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-310    2-[(2-methylphenyl)amino]-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-311    2-[(2-methoxyphenyl)amino]-5,7-dihydro-6H-[1]benzofuro[3,2-b]pyrimido[4,5-d]azepin-6-one-   I-312    2-[(2-fluorophenyl)amino]-5,7-dihydro-6H-[1]benzofuro[3,2-b]pyrimido[4,5-d]azepin-6-one-   I-313    2-[(2-methylphenyl)amino]-5,7-dihydro-6H-[1]benzofuro[3,2-b]pyrimido[4,5-d]azepin-6-one-   I-314    2-({4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[4,5-d]thieno[3,2-b]azepin-6-one-   I-315    9-chloro-2-{[4-(1H-imidazol-1-yl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-316    9-chloro-2-{[3-(4-methylpiperazin-1-yl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-317    9-chloro-2-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-318    9-chloro-2-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-319    2-[(2-aminophenyl)amino]-10-(3-pyrrolidin-1-ylpropyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-320    2-({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amino)-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-321    2-({4-[(3-methylpiperazin-1-yl)carbonyl]phenyl}amino)-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-322    N-[2-(dimethylamino)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-2-yl)amino]benzamide-   I-323    2-[(4-{[3-(dimethylamino)pyrrolidin-1-yl]carbonyl]phenyl)amino}-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-324    4-methyl-N-(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)benzamide-   I-325    2-({4-[(3-aminopyrrolidin-1-yl)carbonyl]phenyl}amino)-5H-pyrimido[4,5-d]thieno[3,4-b]azepin-6(7H)-one-   I-326    2-[(3,4-dimethoxyphenyl)amino]-8-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-327    8-methyl-2-{[3-(4-methylpiperazin-1-yl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-328    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzoic    acid-   I-329    9-chloro-2-[(3-methylbutyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-330    9-chloro-2-(propylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-331    9-chloro-7-methyl-2-[(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-332    9-chloro-2-{[2-(2-thienyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-333 methyl    (2R)-2-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]propanoate-   I-334    9-chloro-2-{[2-(5-chloro-1H-indol-3-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-335    2-{[(2-bromo-3-thienyl)methyl]amino}-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-336    9-chloro-2-[(2-thienylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-337    3-{2-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]ethyl}-2-methyl-1H-indole-5-carbonitrile-   I-338    9-chloro-2-[(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-339    2-[(1,3-benzodioxol-5-ylmethyl)amino]-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-340    9-chloro-2-[(3-methoxybenzyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-341    9-chloro-2-{[3-(1H-imidazol-1-yl)propyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-342    9-chloro-2-{[2-(2-methyl-1H-indol-3-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-343    9-chloro-2-[(2,3-dihydro-1-benzofuran-5-ylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-344    9-chloro-2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-345    9-chloro-2-{[(2-methyl-1,3-thiazol-4-yl)methyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-346    9-chloro-2-[(2-pyridin-2-ylethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-347    9-chloro-2-{[(5-methyl-2-furyl)methyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-348    9-chloro-2-[(3-furylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-349    9-chloro-2-{[2-(5-methoxy-1H-indol-3-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-350    9-chloro-2-[(2-phenylethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-351    9-chloro-2-{[2-(4-fluorophenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-352    9-chloro-2-{[2-(4-methylphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-353 ethyl    (2S)-2-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]propanoate-   I-354    9-chloro-2-{[(5-pyridin-2-yl-2-thienyl)methyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-355    9-chloro-2-({3-[methyl(phenyl)amino]propyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-356    9-chloro-2-{[2-(2,4-dimethylphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-357    2-(benzylamino)-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-358    9-chloro-2-{[2-(1H-indol-3-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-359    9-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-360 methyl    (2R)-2-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-3-phenylpropanoate-   I-361    9-chloro-2-{[2-(3-methoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-362    9-chloro-2-{[2-(2,4-dichlorophenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-363    9-chloro-2-[(2-furylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-364    4-[(6-oxo-6,7-dihydro-5H-pyrido[3,4-b]pyrimido[4,5-d]azepin-2-yl)amino]benzoic    acid-   I-365    2-[(3,4-dimethoxyphenyl)amino]-5,7-dihydro-6H-pyrido[3,4-b]pyrimido[4,5-d]azepin-6-one-   I-366    2-[(4-methylphenyl)amino]-5,7-dihydro-6H-pyrido[3,4-b]pyrimido[4,5-d]azepin-6-one-   I-367    2-[(3,4-dichlorophenyl)amino]-5,7-dihydro-6H-pyrido[3,4-b]pyrimido[4,5-d]azepin-6-one-   I-368    2-[(2-methylphenyl)amino]-5,7-dihydro-6H-pyrido[3,4-b]pyrimido[4,5-d]azepin-6-one-   I-369    2-anilino-5,7-dihydro-6H-pyrido[3,4-b]pyrimido[4,5-d]azepin-6-one-   I-370    9-chloro-7-ethyl-2-[(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-371    9-chloro-7-isopropyl-2-[(4-{[3-(methylamino)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-372    N-(3-isopropoxypropyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-373    N-isopropyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-374    N-(4-fluorobenzyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-375    2-{[4-(pyrrolidin-1-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-376    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(tetrahydrofuran-2-ylmethyl)benzamide-   I-377    2-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-378    N,N-diethyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-379    2-({4-[(4-methylpiperidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-380    N-isobutyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-381    N-(3,5-dimethylisoxazol-4-yl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-382    N-[(1R)-1-cyclohexylethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-383    N-(1-ethynylcyclohexyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-384    2-({4-[(4-acetylpiperazin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-385    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-thienylmethyl)benzamide-   I-386    N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-387    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(tetrahydro-2H-pyran-4-ylmethyl)benzamide-   I-388    N-(2-furylmethyl)-N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-389    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(2-thienyl)ethyl]benzamide-   I-390    2-[(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-391    N-[(5-methyl-2-furyl)methyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-392    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-pyridin-3-ylbenzamide-   I-393    N-cyclopentyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-394    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-propoxypropyl)benzamide-   I-395    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-phenylethyl)benzamide-   I-396    N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-397    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide-   I-398    N-(4-methoxyphenyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-399    2-({4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl)amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-400    N-(2-methoxy-1-methylethyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-401    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-pyridin-2-ylethyl)benzamide-   I-402    N-[(1-ethylpyrrolidin-3-yl)methyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-ylamino]benzamide-   I-403    2-({4-[(3-oxopiperazin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-404    4-{4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzoyl}-1,4-diazepane-1-carbaldehyde-   I-405    N-(cyclohexylmethyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-406    N-(3-furylmethyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-407    2-({4-[(2-ethylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-408    N-(3-methylbutyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-409    N-(2-cyanoethyl)-N-cyclopropyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-410    N-(cyclopropylmethyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-411    2-[(4-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-412    2-({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-413    N-cyclohexyl-N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-414    N-(2-cyanoethyl)-N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-415    2-{[4-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-416    N-[3-(1H-imidazol-1-yl)propyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-417    N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-prop-2-yn-1-ylbenzamide-   I-418    N-[2-(dimethylamino)ethyl]-N-ethyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-419    N-[2-(acetylamino)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-420    N-(2-methoxyethyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-421    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-piperidin-1-ylethyl)benzamide-   I-422    N-cyclohexyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-423    N-[2-(dimethylamino)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-424    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyridin-2-ylmethyl)benzamide-   I-425    N-[2-(diethylamino)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-426    N-methyl-N-(1-methylpiperidin-4-yl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-427    N-[2-(dimethylamino)ethyl]-N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-428    N-methyl-N-(1-methylpyrrolidin-3-yl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-429    2-{[4-(piperidin-1-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-430    N-[(2-methyl-1,3-thiazol-4-yl)methyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-431    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-pyrrolidin-1-ylpropyl)benzamide-   I-432    2-{[4-(azetidin-1-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-433    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyridin-4-ylmethyl)benzamide-   I-434    N-(2-isopropoxyethyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-435    2-({4-[(2-isobutylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-436    N-(4,6-dimethylpyridin-2-yl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-437    N-(2-morpholin-4-ylethyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-438    2-({4-[(5-ethyl-2-methylpiperidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-439    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-(1-methylpyrrolidin-3-yl)benzamide-   I-440    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2,2-dimethylpropyl)benzamide-   I-441    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-ethoxyethyl)benzamide-   I-442    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(diethylamino)ethyl]benzamide-   I-443    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-cyclohexylbenzamide-   I-444    2-{[4-(azetidin-1-ylcarbonyl)phenyl]amino}-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-445    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1H-imidazol-2-ylmethyl)benzamide-   I-446    9-chloro-2-({4-[(3,5-dimethylpiperidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-447    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-cyclopropylbenzamide-   I-448    9-chloro-2-{[4-(piperidin-1-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-449    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(tetrahydrofuran-2-ylmethyl)benzamide-   I-450    9-chloro-2-({4-[(3-methoxypiperidin-1-yl)carbonyl]phenyl)amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-451    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(4-methyl-1H-imidazol-2-yl)methyl]benzamide-   I-452    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-propylbenzamide-   I-453    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1-methylbutyl)benzamide-   I-454    N-butyl-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-455    9-chloro-2-{[4-(pyrrolidin-1-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-456    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-pyridin-4-ylbenzamide-   I-457    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(dimethylamino)ethyl]-N-methylbenzamide-   I-458    N-[2-(acetylamino)ethyl]-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-459    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1,3-dioxolan-2-ylmethyl)-N-methylbenzamide-   I-460    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(tetrahydro-2-H-pyran-4-ylmethyl)benzamide-   I-461    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-methylcyclohexyl)benzamide-   I-462    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-cyclohexyl-N-methylbenzamide-   I-463    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-isopropoxyethyl)benzamide-   I-464    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyrimidin-4-ylmethyl)benzamide-   I-465    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-pyridin-2-ylethyl)benzamide-   I-466    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-cyanoethyl)-N-cyclopropylbenzamide-   I-467    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3,3-dimethylbutyl)benzamide-   I-468    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-furylmethyl)-N-methylbenzamide-   I-469    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-cyclopentylbenzamide-   I-470    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-methylbenzyl)benzamide-   I-471    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-isobutylbenzamide-   I-472    9-chloro-2-[(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-473    N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-474    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-isopropoxypropyl)benzamide-   I-475    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1,3-dioxolan-2-ylmethyl)benzamide-   I-476    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-methyl-1,3-oxazol-2-yl)benzamide-   I-477    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1H-imidazol-2-ylmethyl)-N-methylbenzamide-   I-478    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-methylbutyl)benzamide-   I-479    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-methylbenzyl)benzamide-   I-480    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyridin-2-ylmethyl)benzamide-   I-481    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-isopropylbenzamide-   I-482    9-chloro-2-({4-[(2-ethylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-483    N-benzyl-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-484    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(dimethylamino)-1-methylethyl]benzamide-   I-485    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N,N-diethylbenzamide-   I-486    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1,3-dimethyl-1H-pyrazol-5-yl)benzamide-   I-487    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-methoxyphenyl)benzamide-   I-488    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-thienylmethyl)benzamide-   I-489    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1-phenylethyl)benzamide-   I-490    9-chloro-2-({4-[(4-methylpiperidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-491    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[1-(methoxymethyl)propyl]benzamide-   I-492    9-chloro-2-({4-[(2-methylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-493    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-methoxy-1-methylethyl)benzamide-   I-494    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-prop-2-yn-1-ylbenzamide-   I-495    9-chloro-2-({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-496    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3,5-dimethylisoxazol-4-yl)benzamide-   I-497    9-chloro-2-({4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-498    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[3-(dimethylamino)propyl]-N-methylbenzamide-   I-499    9-chloro-2-({4-[(3,4-dimethylpiperazin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-500    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-pyridin-3-ylbenzamide-   I-501    9-chloro-2-[(4-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-502    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(cyclopropylmethyl)benzamide-   I-503    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-isopropyl-N-methylbenzamide-   I-504    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-methoxypropyl)benzamide-   I-505    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-ethoxypropyl)benzamide-   I-506    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-cyanoethyl)-N-methylbenzamide-   I-507    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-methoxyethyl)benzamide-   I-508    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-1H-indol-5-ylbenzamide-   I-509    N-1,3-benzodioxol-5-yl-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-510    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-[(5-methyl-1H-pyrazol-3-yl)methyl]benzamide-   I-511    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-isobutoxypropyl)benzamide-   I-512    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(1R)-1-cyclohexylethyl]benzamide-   I-513    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[1-(4-methyl-1,3-thiazol-2-yl)ethyl]benzamide-   I-514    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(methylsulfonyl)ethyl]benzamide-   I-515    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-(3-thienylmethyl)benzamide-   I-516    9-chloro-2-({-4-[(5-fluoro-2,3-dihydro-1H-indol-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-517    2-({4-[(4-acetylpiperazin-1-yl)carbonyl]phenyl}amino)-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-518    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-fluoro-4-methoxyphenyl)benzamide-   I-519    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2,5-difluorobenzyl)benzamide-   I-520    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(1-ethylpyrrolidin-3-yl)methyl]benzamide-   I-521    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[1-(2-methyl-1,3-thiazol-4-yl)ethyl]benzamide-   I-522    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2,3-dihydro-1-benzofuran-5-ylmethyl)benzamide-   I-523    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzamide-   I-524    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][f]benzazepin-2-yl)amino]-N-[2-(5-methyl-4H-1,2,4-triazol-3-yl)ethyl]benzamide-   I-525    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(1S)-1-(4-methylphenyl)ethyl]benzamide-   I-526    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide-   I-527    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][f]benzazepin-2-yl)amino]-N-(2-methoxy-5-methylphenyl)benzamide-   I-528    9-chloro-2-[(4-{[2-(2-furyl)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-529    9-chloro-2-({4-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-530    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(1-methylpyrrolidin-2-yl)ethyl]benzamide-   I-531    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[3-(1H-imidazol-1-yl)propyl]benzamide-   I-532    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-(1-methylpiperidin-4-yl)benzamide-   I-533    N-1-azabicyclo[2.2.2]oct-3-yl-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-534    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[3-(dimethylamino)phenyl]benzamide-   I-535    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-(tetrahydro-2H-pyran-4-ylmethyl)benzamide-   I-536    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-methoxy-2-methylphenyl)benzamide-   I-537    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-piperidin-1-ylethyl)benzamide-   I-538    9-chloro-2-({4-[(4-propylpiperazin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-539    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[1-(5-methyl-4H-1,2,4-triazol-3-yl)ethyl]benzamide-   I-540    9-chloro-2-[(4-{[3-(methylsulfonyl)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-541    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(3-fluorophenyl)ethyl]benzamide-   I-542    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(diisopropylamino)ethyl]benzamide-   I-543    9-chloro-2-[(4-{[3-(diethylamino)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-544    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-methoxybenzyl)benzamide-   I-545    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-methoxybenzyl)benzamide-   I-546    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[4-(dimethylamino)phenyl]benzamide-   I-547    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(2-thienyl)ethyl]benzamide-   I-548    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(2-methyl-1,3-thiazol-4-yl)methyl]benzamide-   I-549    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]benzamide-   I-550    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2,2-diethoxyethyl)benzamide-   I-551    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-morpholin-4-ylethyl)benzamide-   I-552    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-[(4-methyl-1H-imidazol-2-yl)methyl]benzamide-   I-553    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(5-ethyl-1,3,4-thiadiazol-2-yl)benzamide-   I-554    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1-ethynylcyclohexyl)benzamide-   I-555    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-methoxyphenyl)benzamide-   I-556    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-[(3-methylisoxazol-5-yl)methyl]benzamide-   I-557    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]benzamide-   I-558    2-({4-[(3-acetylpiperidin-1-yl)carbonyl]phenyl}amino)-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-559    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-oxo-2-phenylethyl)benzamide-   I-560    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N,N-dimethylbenzamide-   I-561    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(diethylamino)ethyl]-N-methylbenzamide-   I-562    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-morpholin-4-ylpropyl)benzamide-   I-563    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(1S)-2-phenylcyclopropyl]benzamide-   I-564    9-chloro-2-({4-[(2-isobutylpyrrolidin-1-yl)carbonyl]phenyl)amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-565    9-chloro-2-({4-[(5-ethyl-2-methylpiperidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-566    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(6-methoxypyridin-3-yl)benzamide-   I-567    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[3-(dimethylamino)-2,2-dimethylpropyl]benzamide-   I-568    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-pyrrolidin-1-ylpropyl)benzamide-   I-569    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[1-(4-fluorophenyl)ethyl]benzamide-   I-570    9-chloro-2-[(4-morpholin-4-ylbenzyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-571    N-isopropyl-N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-572    2-({4-[(2-methylaziridin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-573    2-({4-[(2-methylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-574    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-phenylbenzamide-   I-575    9-chloro-2-{[2-(1-methylpyrrolidin-2-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-576    2-({4-[(2-pyridin-4-ylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-577    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzamide-   I-578    N-(3-isobutoxypropyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-579    N-(2-fluorobenzyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-580    N-[(1S)-1-(4-methylphenyl)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-581    N-(2-fluorophenyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-582    2-{[4-(2,3-dihydro-1H-indol-1-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-583    N-1,3-benzodioxol-5-yl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-584    2-({4-[(3-methylpiperidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-585    N-(1,3-dihydro-2-benzofuran-5-yl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-586    N-(4-methoxybenzyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-587    N-[2-(diethylamino)ethyl]-N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-588    N-(3-morpholin-4-ylpropyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-589    N-[3-(dimethylamino)propyl]-N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-590    2-{[4-(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-591    N-(2,4-dimethylbenzyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-592    N-[3-(dimethylamino)-2,2-dimethylpropyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-593    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-pyridin-4-ylbenzamide-   I-594    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-phenoxyethyl)benzamide-   I-595    2-({4-[(2-pyridin-2-ylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-596    N-(2-cyanoethyl)-N-cyclopentyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-597    N-methyl-N-(1-{4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzoyl}pyrrolidin-3-yl)acetamide-   I-598    N-[2-(3,4-dimethylphenyl)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-599    N-(2,5-difluorobenzyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-600    N-1H-indol-5-yl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-601    N-(4-methyl-1,3-thiazol-2-yl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-602    2-[(4-{[3-(diethylamino)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-603    N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-604    2-({4-[(5-fluoro-2,3-dihydro-1H-indol-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-605    N-(2-methyl-1H-indol-5-yl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-606    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-phenylpropyl)benzamide-   I-607    N-(3-methoxyphenyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-608    N-ethyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyridin-4-ylmethyl)benzamide-   I-609    N-(3-methoxybenzyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-610    N-[1-(4-fluorophenyl)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-611    2-({4-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-612    2-({4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-613    N-[4-(dimethylamino)phenyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-614    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-quinolin-3-ylbenzamide-   I-615    N-(4-fluorobenzyl)-N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-616    N-(cyclopropylmethyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-propylbenzamide-   I-617    2-[4-{[3-(methylsulfonyl)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-618    N-[2-(diisopropylamino)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-619    N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-pyridin-2-ylethyl)benzamide-   I-620    N-ethyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-pyridin-2-ylethyl)benzamide-   I-621    N-[2-(diethylamino)ethyl]-N-ethyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-622    N-(5-methyl-1,3-thiazol-2-yl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-623    N-(4-chlorobenzyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-624    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-pyrrolidin-1-ylbutyl)benzamide-   I-625    2-{[2-(2-fluorophenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-626    2-{[2-(trifluoromethyl)benzyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-627    2-{[(1S)-1-(3-methoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-628    2-[(2-fluoro-5-methylphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-629    2-[(2-methoxy-1-methylethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-630    2-[(6-chloropyridin-3-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-631    2-(cyclohexylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-632    2-[(2-phenylpropyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-633    2-[(4-methylpyridin-2-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-634    2-[(2,6-dimethoxypyridin-3-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-635    2-(cyclobutylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-636    2-[(3-isopropoxypropyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-637    2-{[4-(trifluoromethyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-638    2-[(4-morpholin-4-ylphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-639    2-(2,3-dihydro-1,4-benzodioxin-6-ylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-640    2-{[3-(trifluoromethyl)benzyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-641    2-[(3-pyrrolidin-1-ylpropyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-642    2-[(2-isopropoxyethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-643    2-{[(1S,2R)-2-hydroxy-1-methyl-2-phenylethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-644    2-{[(1S)-1-phenylethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-645    2-[(2,4-difluorophenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-646    2-[(3-methylbutyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-647    2-[(3-bromo-5-methylpyridin-2-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-648    2-[(6-methoxypyridin-3-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-649    2-[(3,5-dimethoxyphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-650    2-(1,3-benzodioxol-5-ylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-651    2-[(trans-4-hydroxycyclohexyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-652    2-{[1-(4-chlorobenzyl)-2-hydroxyethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-653    2-(pyrimidin-2-ylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-654    2-[(4-methoxy-2-methylphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-655    2-[(3-chloro-4-fluorophenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-656    2-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-657    2-{[3-(2-methylpiperidin-1-yl)propyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-658    2-{[2-(difluoromethoxy)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-659    2-{[3-fluoro-5-(trifluoromethyl)benzyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-660    2-[(5-chloropyridin-2-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-661 ethyl    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]piperidine-1-carboxylate-   I-662    2-{[2-(trifluoromethyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-663    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]benzamide-   I-664    9-chloro-2-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-665    9-chloro-2-{[4-(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-666    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(1,3-dioxolan-2-yl)ethyl]benzamide-   I-667    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-phenylbenzamide-   I-668    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1,3-dihydro-2-benzofuran-5-yl)benzamide-   I-669    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[1-(hydroxymethyl)-2-methylpropyl]benzamide-   I-670    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(dimethylamino)ethyl]benzamide-   I-671    N-(3-acetylphenyl)-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-672    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2,2-dimethoxyethyl)-N-methylbenzamide-   I-673    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-cyclobutylbenzamide-   I-674    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(6-methylpyridin-2-yl)benzamide-   I-675    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-fluorobenzyl)benzamide-   I-676    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methylbenzamide-   I-677    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-(2-thienylmethyl)benzamide-   I-678    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4,5-dihydro-1,3-thiazol-2-yl)benzamide-   I-679    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(1R)-2,3-dihydro-1H-inden-1-yl]benzamide-   I-680    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[cyano(phenyl)methyl]benzamide-   I-681    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2,3-dimethylcyclohexyl)benzamide-   I-682    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-fluoro-2-methylphenyl)benzamide-   I-683    2-[(3-methoxypropyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-684    2-[(2-phenylethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-685    2-{[2-(diethylamino)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-686    2-[(2-methoxyphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-687    2-[(2-methoxybenzyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-688    2-({3-[methyl(phenyl)amino]propyl}-amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-689    2-[(2-phenoxyethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-690    2-[(2,2-dimethylpropyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-691    2-[(tetrahydrofuran-2-ylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-692    2-(cyclopentylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-693    2-(propylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-694    2-(prop-2-yn-1-ylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-695    2-[(3,3-dimethylbutyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-696    2-[(1,3,5-trimethyl-1H-pyrazol-4-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-697    2-{[2-(3,4-dimethylphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-698    2-[(3-morpholin-4-ylpropyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-699    2-[(2-ethoxyethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-700    2-[(2-piperidin-1-ylethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-701    2-[(pyridin-2-ylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-702    2-[(2-fluorobenzyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-703    2-[(4-chloro-2-fluorophenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-704    2-(isopropylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-705    2-[(cyclohexylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-706    2-[(1H-benzimidazol-2-ylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-707    2-{[1-(4-methyl-1,3-thiazol-2-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-708    2-{[1-(methoxymethyl)propyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-709    2-{[(2-bromo-3-thienyl)methyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-710    2-{[3-(trifluoromethoxy)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-711    2-{[2-(4-fluorophenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-712    2-{[2-(methylsulfonyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-713    2-{[(3-methyl-2-thienyl)methyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-714    2-{[2-(2,4-dichlorophenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-715    2-[(2,5-difluorobenzyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-716    2-{[4-(methylsulfanyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-717    2-(1H-indol-5-ylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-718    2-[(3-fluoro-4-methoxyphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-719    2-{[2-(2,5-dimethylphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-720    2-{[2-(5-chloro-1H-indol-3-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-721    2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-722    2-{[(1R)-1-cyclohexylethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-723    2-[(cyclopropylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-724    2-{[(1-ethylpyrrolidin-3-yl)methyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-725    2-{[2-(5-chloro-1H-benzimidazol-2-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-726    2-{[2-(4-aminophenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-727    2-[(4-fluorobenzyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-728    2-{[2-(2-thienyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-729    2-[(1-methylbutyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-730    2-{[2-(3-fluorophenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-731    2-{[(5-chloro-1-benzothien-3-yl)methyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-732    2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-733    2-{[2-(diisopropylamino)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-734    2-{[2-(2,4-dimethylphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-735    2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-736    2-[(3-methoxybenzyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-737    2-[(2-methylcyclohexyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-738    2-methyl-3-{2-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]ethyl}-1H-indole-5-carbonitrile-   I-739    2-{[2-(5-methoxy-1H-indol-3-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-740    2-[(1,3-benzodioxol-5-ylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-741    2-(quinolin-3-ylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-742    2-{[3-(1H-imidazol-1-yl)propyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-743    2-(benzylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-744    2-{[(1S)-2-phenylcyclopropyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-745    2-(ethylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-746    2-[(4-methylcyclohexyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-747    2-{[3-(dimethylamino)-2,2-dimethylpropyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-748    2-[(2-chloro-4-methylphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-749    2-{[3-(dimethylamino)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-750    2-{[2-(4-methylphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-751    2-{[(5-methyl-2-furyl)methyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-752    2-[(2-furylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-753    2-{[2-(dimethylamino)-1-methylethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-754    2-(1,3-dihydro-2-benzofuran-5-ylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-755    N-cyclohexyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-756    N-[2-(dimethylamino)ethyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-757    N-methyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-pyridin-2-ylethyl)benzamide-   I-758    N-isopropyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-759    N-[2-(dimethylamino)ethyl]-N-ethyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-760    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-quinolin-2-ylbenzamide-   I-761    N-(3-isopropoxypropyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-762    2-({4-[(4-acetylpiperazin-1-yl)carbonyl]phenyl}amino)-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-763    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-piperidin-1-ylethyl)benzamide-   I-764    N-(1-ethynylcyclohexyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-765    N-(4-methoxybenzyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-766    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-phenylethyl)benzamide-   I-767    N-cyclohexyl-N-methyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-768    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-methyl-1,3-thiazol-2-yl)benzamide-   I-769    7-methyl-2-({4-[(4-methylpiperidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-770    N-1H-indol-5-yl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-771    N-(2-isopropoxyethyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-772    N-(cyclopropylmethyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-773    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide-   I-774    N-[4-(dimethylamino)phenyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-775    2-[(4-{[3-(diethylamino)pyrrolidin-1-yl]carbonyl}phenyl)amino]-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-776    2-[(4-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}phenyl)amino]-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-777    N-[2-(diethylamino)ethyl]-N-ethyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-778    N-(3,5-dimethylisoxazol-4-yl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-779    N-(2-fluorobenzyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-780    2-[(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]carbonyl}phenyl)amino]-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-781    2-({4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}amino)-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-782    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyridin-4-ylmethyl)benzamide-   I-783    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-pyridin-4-ylbenzamide-   I-784    N-(2-methoxy-1-methylethyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-785    2-{[4-(2,3-dihydro-1H-indol-1-ylcarbonyl)phenyl]amino}-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-786    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(1S)-1-(4-methylphenyl)ethyl]benzamide-   I-787    N-(2,4-dimethylbenzyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-788    4-{4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzoyl}-1,4-diazepane-1-carbaldehyde-   I-789    N-[(1R)-2,3-dihydro-1H-inden-1-yl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-790    N-ethyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyridin-4-ylmethyl)benzamide-   I-791    N-[2-(acetylamino)ethyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-792    7-methyl-2-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-793    N-(4-methoxyphenyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-794    N-[(1-ethylpyrrolidin-3-yl)methyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-795    N-[(5-methyl-2-furyl)methyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-796    7-methyl-2-({4-[(3-oxopiperazin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-797    N-cyclopentyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-798    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(2-thienyl)ethyl]benzamide-   I-799    N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-800    2-{[4-(3,4-dihydroisoquinolin-2(1H)-ylcarbonyl)phenyl]amino}-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-801    N-methyl-N-(1-{4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzoyl}pyrrolidin-3-yl)acetamide-   I-802    N-(3-methylbutyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-803    N-(2-cyanoethyl)-N-cyclopropyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-804    N,N-diethyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-805    N-[3-(1H-imidazol-1-yl)propyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-806    N-[3-(dimethylamino)-2,2-dimethylpropyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-807    N-ethyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-pyridin-2-ylethyl)benzamide-   I-808    7-methyl-2-{[4-(pyrrolidin-1-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-809    N-(4-fluorobenzyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-810    2-({4-[(2-isobutylpyrrolidin-1-yl)carbonyl]phenyl}amino)-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-811    7-methyl-2-({4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-812    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(tetrahydrofuran-2-ylmethyl)benzamide-   I-813    N-(2-methyl-1H-indol-5-yl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-814    N-(2-furylmethyl)-N-methyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-815    N-(cyclohexylmethyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-816    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-phenoxyethyl)benzamide-   I-817    2-({4-[(5-ethyl-2-methylpiperidin-1-yl)carbonyl]phenyl}amino)-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-818    N-(2-methoxyethyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-819    N-(2-cyanoethyl)-N-methyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-820    N-(3-isobutoxypropyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-821    2-{[4-(1,3-dihydro-2H-isoindol-2-ylcarbonyl)phenyl]amino}-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-822    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-propoxypropyl)benzamide-   I-823    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[4-(methylsulfanyl)phenyl]benzamide-   I-824    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-pyridin-3-ylbenzamide-   I-825    2-({4-[(5-fluoro-2,3-dihydro-1H-indol-1-yl)carbonyl]phenyl}amino)-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-826    2-({4-[(2-ethylpyrrolidin-1-yl)carbonyl]phenyl}amino)-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-827    N-[2-(diisopropylamino)ethyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-828    N-(2-cyanoethyl)-N-cyclopentyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-829    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzamide-   I-830    7-methyl-2-({4-[(3-methylpiperidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-831    7-methyl-2-{[4-(piperidin-1-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-832    N-(4-chlorobenzyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-833    N-(2,5-difluorobenzyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-834    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(1,3,5-trimethyl-1H-pyrazol-4-yl)methyl]benzamide-   I-835    2-({4-[(4-butylpiperazin-1-yl)carbonyl]phenyl}amino)-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-836    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-ethyl-N-(2-pyridin-2-ylethyl)benzamide-   I-837    4-{4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzoyl}-1,4-diazepane-1-carbaldehyde-   I-838    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-fluoro-3-methylphenyl)benzamide-   I-839    9-chloro-2-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-ylcarbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-840    N-(1-{4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzoyl}pyrrolidin-3-yl)-N-methylacetamide-   I-841    N-(2-chloro-4-methylphenyl)-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-842    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-methyl-1H-benzimidazol-6-yl)benzamide-   I-843    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-ethoxyphenyl)benzamide-   I-844    N-butyl-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-cyanoethyl)benzamide-   I-845    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-fluorobenzyl)benzamide-   I-846    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-chloropyridin-4-yl)benzamide-   I-847    N-(1H-benzimidazol-2-ylmethyl)-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-848    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-ethylbenzyl)-N-methylbenzamide-   I-849    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-phenoxyethyl)benzamide-   I-850    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-ethoxyphenyl)benzamide-   I-851    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(cyclopropylmethyl)-N-propylbenzamide-   I-852    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(dimethylamino)ethyl]-N-ethylbenzamide-   I-853    9-chloro-2-({4-[(6-methyl-3,4-dihydroquinolin-1(2H)-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-854    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-isoquinolin-1-ylbenzamide-   I-855    9-chloro-2-({4-[(2-pyridin-4-ylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-856    9-chloro-2-({4-[(2-ethylpiperidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-857    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-fluorobenzyl)-N-methylbenzamide-   I-858    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-phenylbenzamide-   I-859    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-chlorophenyl)-N-methylbenzamide-   I-860    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2,4-difluorophenyl)-N-methylbenzamide-   I-861    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-methoxyphenyl)benzamide-   I-862    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-ethyl-6-methylpyridin-2-yl)benzamide-   I-863    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-chlorophenyl)benzamide-   I-864    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-(2-pyridin-2-ylethyl)benzamide-   I-865    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-phenylpropyl)benzamide-   I-866    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(2,5-dimethylphenyl)ethyl]benzamide-   I-867    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1-phenylpropyl)benzamide-   I-868    9-chloro-2-[(4-{[2-(2-methoxyethyl)piperidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-869    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(4-fluorophenyl)ethyl]benzamide-   I-870    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-fluoro-5-methylphenyl)benzamide-   I-871    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3,3,5-trimethylcyclohexyl)benzamide-   I-872    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-[(2-methyl-1,3-thiazol-4-yl)methyl]benzamide-   I-873    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-methoxybenzyl)benzamide-   I-874    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-phenylpropyl)benzamide-   I-875    9-chloro-2-({4-[(2-pyridin-3-ylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-876    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-cyclohexyl-N-ethylbenzamide-   I-877    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)benzamide-   I-878    N-(4-chlorobenzyl)-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-879    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-pyrrolidin-1-ylbutyl)benzamide-   I-880    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-furylmethyl)benzamide-   I-881    9-chloro-2-({4-[(2-pyridin-2-ylpyrrolidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-882    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(6-chloropyridin-3-yl)benzamide-   I-883    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(3,4-dimethylphenyl)ethyl]benzamide-   I-884    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(2-fluorophenyl)ethyl]benzamide-   I-885    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-isopropylphenyl)benzamide-   I-886    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-cyclooctylbenzamide-   I-887    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(1,3-dioxolan-2-yl)ethyl]-N-methylbenzamide-   I-888    9-chloro-2-({4-[(2-methyl-2,3-dihydro-1H-indol-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-889    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-[1-(2-thienyl)ethyl]benzamide-   I-890    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-methylpyridin-2-yl)benzamide-   I-891    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-(4-methylbenzyl)benzamide-   I-892    2-{[4-(6-azabicyclo[3.2.1]oct-6-ylcarbonyl)phenyl]amino}-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-893    7-methyl-2-{[4-(morpholin-4-ylsulfonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-894    N-cyclopentyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-895    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(2R)-2-phenylpropyl]benzamide-   I-896    2-[(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]carbonyl}phenyl)amino]-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-897    2-({4-[(4-ethylpiperazin-1-yl)carbonyl]phenyl}amino)-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-898    N-(2-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]ethyl)acetamide-   I-899    2-{[2-(4-ethylphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-900    2-({[(2S)-ethylpyrrolidin-2-yl]methyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-901    2-{[2-(3-chlorophenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-902    2-[(2-pyridin-2-ylethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-903    2-{[2-(4-chlorophenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-904    2-{[2-(3-methoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-905    2-{[2-(4-methoxyphenoxy)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-906    2-(2,1,3-benzoxadiazol-4-ylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-907    2-{[2-(4-phenoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-908    2-{[2-(2-phenoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-909    2-{[2-(3-ethoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-910    2-(quinolin-6-ylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-911    2-[(3-isobutoxypropyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-912    2-[(2-cyclohex-1-en-1-ylethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-913    2-{[2-(3,5-dimethoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-914    2-{[2-(3-ethoxy-4-methoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-915    2-[(3-ethoxypropyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-916    2-{[2-(2,6-dichlorophenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-917    2-{[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-918    2-{[2-(3-bromo-4-methoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-919    2-{[2-(1-methylpyrrolidin-2-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-920    2-{[2-(2-chlorophenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-921    2-{[3-(cyclohexylamino)propyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-922    2-[(3-phenylpropyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-923    2-({2-pyrrolidin-1-yl-2-[4-(trifluoromethyl)phenyl]ethyl)amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-924    2-{[2-(4-bromophenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-925    2-{[1-(hydroxymethyl)-2-methylpropyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-926    2-{[2-(4-ethoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-927    2-{[2-(pyridin-3-yloxy)propyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-928    2-({2-(dimethylamino)-2-[4-(trifluoromethyl)phenyl]ethyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-929    2-({[5-methyl-2-(trifluoromethyl)-3-furyl]methyl)amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-930    2-[(4-pyrrolidin-1-ylbutyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-931    2-({2-[3-(dimethylamino)phenoxy]propyl)amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-932    2-{[4-(diethylamino)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-933    2-{[2,4-dimethoxy-5-(trifluoromethyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-934    2-{[2-(2-fluorophenoxy)pyridin-3-yl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-935    2-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-936    2-[(4-piperidin-1-ylphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-937    2-[(2-pyrrolidin-1-ylethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-938    N,N-dimethyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-939    2-[(2-aminophenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-940    2-({2-[ethyl(3-methylphenyl)amino]ethyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-941    2-{[4-(1,3-oxazol-5-yl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-942    2-[(pyridin-4-ylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-943    2-{[2-(2,3-dimethylphenoxy)pyridin-3-yl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-944    2-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-945    2-{[3-methoxy-5-(trifluoromethyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-946    (2S)-1-({4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}sulfonyl)pyrrolidine-2-carboxamide-   I-947    N-[3-(dimethylamino)propyl]-N-methyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-948    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-prop-2-yn-1-ylbenzenesulfonamide-   I-949    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-morpholin-4-ylpropyl)benzenesulfonamide-   I-950    N-(2-cyanoethyl)-N-cyclopentyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-951    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-phenylethyl)benzenesulfonamide-   I-952    N-(4-fluorobenzyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-953    2-({4-[(2-ethylpyrrolidin-1-yl)sulfonyl]phenyl}amino)-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-954    2-[(4-{-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}phenyl)amino]-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-955    N-[2-(3,4-dimethylphenyl)ethyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-956    7-methyl-2-({4-[(3-methylpiperidin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-957    N-(3-methylbutyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-958    N-(3-isopropoxypropyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-959    N-methyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1-methylpyrrolidin-3-yl)benzenesulfonamide-   I-960    N-[1-(methoxymethyl)propyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-961    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyridin-4-ylmethyl)benzenesulfonamide-   I-962    N-[2-(diethylamino)ethyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-963    N-methyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-prop-2-yn-1-ylbenzenesulfonamide-   I-964    N-cyclohexyl-N-methyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-965    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-phenylbenzenesulfonamide-   I-966    7-methyl-2-({4-[(2-methylpyrrolidin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-967    N-[2-(dimethylamino)ethyl]-N-methyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-968    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(tetrahydrofuran-2-ylmethyl)benzenesulfonamide-   I-969    N-methyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1-methylpiperidin-4-yl)benzenesulfonamide-   I-970    N-cyclohexyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-971    N-benzyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-972    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(1-ethylpyrrolidin-3-yl)methyl]benzenesulfonamide-   I-973    N-[2-(diisopropylamino)ethyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-974    9-chloro-2-({4-[(2-methylpyrrolidin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-975    N,N-diethyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-976    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-phenylethyl)benzenesulfonamide-   I-977    N-methyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-pyridin-2-ylethyl)benzenesulfonamide-   I-978    9-chloro-2-[(4-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-979    N-(2-methoxy-1-methylethyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-980    4-({-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}sulfonyl)piperazine-1-carbaldehyde-   I-981    N-{2-[({4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}sulfonyl)amino]ethyl}acetamide-   I-982    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-furylmethyl)-N-methylbenzenesulfonamide-   I-983    N-ethyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-pyridin-2-ylethyl)benzenesulfonamide-   I-984    2-({4-[(4-butylpiperazin-1-yl)sulfonyl]phenyl}amino)-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-985    N-(1-ethynylcyclohexyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-986    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-methylbutyl)benzenesulfonamide-   I-987    4-({4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}sulfonyl)piperazine-1-carbaldehyde-   I-988    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[3-(1H-imidazol-1-yl)propyl]benzenesulfonamide-   I-989    4-({4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}sulfonyl)-1,4-diazepane-1-carbaldehyde-   I-990    9-chloro-2-({4-[(5-fluoro-2,3-dihydro-1H-indol-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-991    2-{[4-(2,3-dihydro-1H-indol-1-ylsulfonyl)phenyl]amino}-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-992    9-chloro-2-{[4-(piperidin-1-ylsulfonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-993    7-methyl-2-({4-[(3-oxopiperazin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-994    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-(1-methylpiperidin-4-yl)benzenesulfonamide-   I-995    N-benzyl-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-996    2-[(4-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}phenyl)amino]-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-997    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[1-(methoxymethyl)propyl]benzenesulfonamide-   I-998    7-methyl-2-({4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-999    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-phenylbenzenesulfonamide-   I-1000    N-[2-(3-fluorophenyl)ethyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1001    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-propylbenzenesulfonamide-   I-1002    N-[(1-ethylpyrrolidin-3-yl)methyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1003    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N,N-diethylbenzenesulfonamide-   I-1004    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(2-methyl-1,3-thiazol-4-yl)methyl]benzenesulfonamide-   I-1005    N-{2-[({-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}sulfonyl)amino]ethyl}acetamide-   I-1006    2-({4-[(5-ethyl-2-methylpiperidin-1-yl)sulfonyl]phenyl}amino)-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1007    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[4-(dimethylamino)phenyl]benzenesulfonamide-   I-1008    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(1S)-1-(4-methylphenyl)ethyl]benzenesulfonamide-   I-1009    9-chloro-2-({4-[(4-ethylpiperazin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1010    N-[1-(4-fluorophenyl)ethyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1011    9-chloro-2-{[4-(pyrrolidin-1-ylsulfonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1012    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-phenoxyethyl)benzenesulfonamide-   I-1013    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-prop-2-yn-1-ylbenzenesulfonamide-   I-1014    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-pyrrolidin-1-ylpropyl)benzenesulfonamide-   I-1015    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-ethyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide-   I-1016    N-(cyclopropylmethyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-propylbenzenesulfonamide-   I-1017    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(cyclopropylmethyl)-N-propylbenzenesulfonamide-   I-1018    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyridin-2-ylmethyl)benzenesulfonamide-   I-1019    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(dimethylamino)-1-methylethyl]benzenesulfonamide-   I-1020    7-methyl-2-({4-[(4-methylpiperidin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1021    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-1H-indol-5-ylbenzenesulfonamide-   I-1022    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-piperidin-1-ylethyl)benzenesulfonamide-   I-1023    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-cyclohexylbenzenesulfonamide-   I-1024    2-[(4-([3-(diethylamino)pyrrolidin-1-yl]sulfonyl)phenyl)amino]-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1025    9-chloro-2-[(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1026    N-(2-methoxyethyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1027    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(1S)-1-(4-methylphenyl)ethyl]benzenesulfonamide-   I-1028    2-{[4-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)phenyl]amino}-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1029    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-fluorobenzyl)benzenesulfonamide-   I-1030    N-(cyclopropylmethyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1031    9-chloro-2-{[4-(1,3-dihydro-2-H-isoindol-2-ylsulfonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1032    N-(2-cyanoethyl)-N-cyclopropyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1033    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-prop-2-yn-1-ylbenzenesulfonamide-   I-1034    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzenesulfonamide-   I-1035    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-methoxy-1-methylethyl)benzenesulfonamide-   I-1036    2-({4-[(4-butylpiperazin-1-yl)sulfonyl]phenyl}amino)-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1037    N-[1-({4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}sulfonyl)pyrrolidin-3-yl]-N-methylacetamide-   I-1038    2-({4-[(4-ethylpiperazin-1-yl)sulfonyl]phenyl}amino)-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1039    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(diisopropylamino)ethyl]benzenesulfonamide-   I-1040    N-[3-(1H-imidazol-1-yl)propyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1041    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(1R)-2,3-dihydro-1H-inden-1-yl]benzenesulfonamide-   I-1042    N-(cyclohexylmethyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1043    9-chloro-2-({4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1044    N-[(5-methyl-2-furyl)methyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1045    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(cyclopropylmethyl)benzenesulfonamide-   I-1046    2-[(4-{-[(2R,6S)-2,6-dimethylmorpholin-4-yl]sulfonyl}phenyl)amino]-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1047    9-chloro-2-({4-[(3-methylpiperidin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-1-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1048    N-[2-(dimethylamino)-1-methylethyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1049    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-cyclopentylbenzenesulfonamide-   I-1050    N-isopropyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1051    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(diethylamino)ethyl]-N-ethylbenzenesulfonamide-   I-1052    N-(2-isopropoxyethyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1053    N-(4-chlorobenzyl)-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1054    2-{[4-(azetidin-1-ylsulfonyl)phenyl]amino}-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1055    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-pyrrolidin-1-ylpropyl)benzenesulfonamide-   I-1056    N-[(1R)-1-cyclohexylethyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1057    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[3-(dimethylamino)-2,2-dimethylpropyl]benzenesulfonamide-   I-1058    N-(2-cyanoethyl)-N-methyl-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1059    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(5-methyl-2-furyl)methyl]benzenesulfonamide-   I-1060    7-methyl-2-{[4-(pyrrolidin-1-ylsulfonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1061    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(diethylamino)ethyl]benzenesulfonamide-   I-1062    2-{[4-(1,3-dihydro-2H-isoindol-2-ylsulfonyl)phenyl]amino}-7-methyl-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1063    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(3,4-dimethylphenyl)ethyl]benzenesulfonamide-   I-1064    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-cyanoethyl)-N-cyclopentylbenzenesulfonamide-   I-1065    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1-ethynylcyclohexyl)benzenesulfonamide-   I-1066    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-ethyl-N-(pyridin-4-ylmethyl)benzenesulfonamide-   I-1067    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2,3-dihydro-1-benzofuran-5-ylmethyl)benzenesulfonamide-   I-1068    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(2-methyl-1,3-thiazol-4-yl)methyl]benzenesulfonamide-   I-1069    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(3-fluorophenyl)ethyl]benzenesulfonamide-   I-1070    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-cyanoethyl)-N-methylbenzenesulfonamide-   I-1071    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-isopropoxypropyl)benzenesulfonamide-   I-1072    9-chloro-2-({4-[(4-methylpiperidin-1-yl)sulfonyl]phenyl)amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1073    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-cyanoethyl)-N-cyclopropylbenzenesulfonamide-   I-1074    2-{[4-(azetidin-1-ylsulfonyl)phenyl]amino}-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1075    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[1-(4-fluorophenyl)ethyl]benzenesulfonamide-   I-1076    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-isopropylbenzenesulfonamide-   I-1077    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-(1-methylpyrrolidin-3-yl)benzenesulfonamide-   I-1078    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(2-thienyl)ethyl]benzenesulfonamide-   I-1079    9-chloro-2-[(4-{[3-(diethylamino)pyrrolidin-1-yl]sulfonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1080    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-piperidin-1-ylethyl)benzenesulfonamide-   I-1081    9-chloro-2-({4-[(4,4-dimethyl-1,3-oxazolidin-3-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1082    9-chloro-2-[(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]sulfonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1083    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(dimethylamino)ethyl]-N-methylbenzenesulfonamide-   I-1084    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-methoxybenzyl)benzenesulfonamide-   I-1085    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-methylbutyl)benzenesulfonamide-   I-1086    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-methoxybenzyl)benzenesulfonamide-   I-1087    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide-   I-1088    (2S)-1-({4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}sulfonyl)pyrrolidine-2-carboxamide-   I-1089    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(cyclohexylmethyl)benzenesulfonamide-   I-1090    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-methyl-1H-indol-5-yl)benzenesulfonamide-   I-1091    N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1092    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(dimethylamino)ethyl]benzenesulfonamide-   I-1093    N-(cyclopropylmethyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-propylbenzamide-   I-1094    N-[2-(3,4-dimethylphenyl)ethyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-1095    N-(3-ethyl-6-methylpyridin-2-yl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-1096    N-[1-(4-fluorophenyl)ethyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-1097    N-[(1R)-1-cyclohexylethyl]-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-1098    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-morpholin-4-ylpropyl)benzamide-   I-1099    N-[(1R)-2,3-dihydro-1H-inden-1-yl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-1100    9-chloro-2-[(4-{[4-(2-chlorophenyl)piperazin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1101    9-chloro-2-[(4-{[4-(3-hydroxyphenyl)piperazin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1102    4-(4-{4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzoyl}piperazin-1-yl)benzonitrile-   I-1103    9-chloro-2-[(4-{[(2S)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1104    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-{2-(dimethylamino)-2-[4-(trifluoromethyl)phenyl]ethyl}benzamide-   I-1105    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[4-(diethylamino)phenyl]benzamide-   I-1106    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-pyridin-3-yl-2-pyrrolidin-1-ylethyl)benzamide-   I-1107    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[(5-pyridin-2-yl-2-thienyl)methyl]benzamide-   I-1108    9-chloro-2-({4-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1109    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(4-methoxyphenyl)-2-morpholin-4-ylethyl]benzamide-   I-1110    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-methyl-N-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]benzamide-   I-1111    9-chloro-2-[(4-{[4-(tetrahydrofuran-2-ylcarbonyl)piperazin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1112    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[3-(2-methylpiperidin-1-yl)propyl]benzamide-   I-1113    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(4-methylpiperazin-1-yl)-1-phenylethyl]benzamide-   I-1114    9-chloro-2-[(4-{[4-(3,5-dimethoxyphenyl)piperazin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1115    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-cyanoethyl)-N-cyclopentylbenzamide-   I-1116    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-methyl-2-morpholin-4-ylpropyl)benzamide-   I-1117    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(2-chlorophenyl)-2-(dimethylamino)ethyl]benzamide-   I-1118    9-chloro-2-[(4-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1119    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[4-(4-methylpiperazin-1-yl)phenyl]benzamide-   I-1120 tert-butyl    [3-({4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzoyl}amino)-2,2-dimethylpropyl]carbamate-   I-1121    9-chloro-2-[(4-{[4-(2-ethoxyphenyl)piperazin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1122    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-{5-[(dimethylamino)sulfonyl]-2-methylphenyl}benzamide-   I-1123    N-[2-(4-benzylpiperazin-1-yl)ethyl]-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-1124 9-chloro-2-[(4-1    [4-(3,4-dichlorophenyl)piperazin-1-yl]carbonyl)phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1125    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-{2-[3-(dimethylamino)phenoxy]propyl}benzamide-   I-1126    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-piperidin-1-ylphenyl)benzamide-   I-1127    9-chloro-2-({4-[(4-pyrimidin-2-ylpiperazin-1-yl)carbonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1128    9-chloro-2-[4-{[4-(2-methylphenyl)piperazin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1129    9-chloro-2-{[4-[4-(4-fluorophenyl)piperazin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1130    9-chloro-2-[(4-{[4-(3-methoxyphenyl)piperazin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1131    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(cyanomethyl)-N-methylbenzamide-   I-1132    N-(1-benzylpyrrolidin-3-yl)-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-1133    N-[(1-benzyl-1H-pyrazol-4-yl)methyl]-4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-1134    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(dimethylamino)-2-phenylethyl]benzamide-   I-1135    9-chloro-2-[(4-{[4-(5-chloro-2-methoxyphenyl)piperazin-1-yl]carbonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1136    1-{4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzoyl}-N,N-diethylpiperidine-3-carboxamide-   I-1137    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(dimethylamino)-2-pyridin-3-ylethyl]benzamide-   I-1138    9-chloro-2-{[4-({4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]piperidin-1-yl}carbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1139    9-chloro-2-{[4-({4-[2-(methylsulfonyl)ethyl]piperazin-1-yl}carbonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1140 ethyl    (4-{4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzoyl}piperazin-1-yl)acetate-   I-1141    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-{2-pyrrolidin-1-yl-2-[4-(trifluoromethyl)phenyl]ethyl}benzamide-   I-1142    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyridin-4-ylmethyl)benzamide-   I-1143    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(dimethylamino)-2-(4-methoxyphenyl)ethyl]benzamide-   I-1144    2-{[4-(1H-pyrazol-1-yl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1145    2-(1H-indazol-5-ylamino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1146    2-({4-[ethyl(2-hydroxyethyl)amino]-2-methylphenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1147    2-{[2-(phenylsulfonyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1148    2-{[(1-pyrimidin-2-ylpiperidin-3-yl)methyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1149    2-[(4′-fluorobiphenyl-3-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1150    2-{[2-(benzylsulfanyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1151    2-{[(2-phenyl-2H-1,2,3-triazol-4-yl)methyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1152    2-[(2-phenyl-2-pyrrolidin-1-ylethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1153    2-{[2-(5-bromo-2-methoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1154    2-[(4-{[(2R,6S)-2,6-dimethylmorpholin-4-yl]sulfonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1155    2-({4-[(4-acetylpiperazin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1156    N-[(2-methyl-1,3-thiazol-4-yl)methyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1157    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyridin-2-ylmethyl)benzenesulfonamide-   I-1158    N-[2-(dimethylamino)-1-methylethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1159    N-[(1S)-1-(4-methylphenyl)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1160    N,N-diethyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1161    N-{2-[({4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}sulfonyl)amino]ethyl}acetamide-   I-1162    N-(cyclopropylmethyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1163    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyridin-4-ylmethyl)benzenesulfonamide-   I-1164    N-(3-morpholin-4-ylpropyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1165    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-propylbenzenesulfonamide-   I-1166    N-(3-isopropoxypropyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1167    2-{[4-(pyrrolidin-1-ylsulfonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1168    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-pyrrolidin-1-ylpropyl)benzenesulfonamide-   I-1169    2-({4-[(4-butylpiperazin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1170    2-[(4-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1171    2-({4-[(3-methylpiperidin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1172    4-({4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}sulfonyl)-1,4-diazepane-1-carbaldehyde-   I-1173    2-[(4-{[(3R)-3-(dimethylamino)pyrrolidin-1-yl]sulfonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1174    N-methyl-N-(1-methylpiperidin-4-yl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1175    N-(cyclopropylmethyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-propylbenzenesulfonamide-   I-1176    N-ethyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-pyridin-2-ylethyl)benzenesulfonamide-   I-1177    N-(2-methoxy-1-methylethyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1178    N-(2-cyanoethyl)-N-cyclopentyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1179    N-benzyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1180    N-isopropyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1181    N-[(1-ethylpyrrolidin-3-yl)methyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1182    N-[2-(diethylamino)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1183    2-{[4-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1184    N-(2-methyl-1H-indol-5-yl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1185    N-(4-fluorobenzyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1186    N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1187    N-[3-(1H-imidazol-1-yl)propyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1188    2-{[4-(1,3-dihydro-2H-isoindol-2-ylsulfonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1189    N-[(1R)-1-cyclohexylethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1190    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-phenylbenzenesulfonamide-   I-1191    N-[2-(dimethylamino)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1192    N-[3-(dimethylamino)-2,2-dimethylpropyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1193    4-({4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}sulfonyl)piperazine-1-carbaldehyde-   I-1194    N-[2-(diisopropylamino)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1195    2-({4-[(5-ethyl-2-methylpiperidin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1196    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-prop-2-yn-1-ylbenzenesulfonamide-   I-1197    N-(2-furylmethyl)-N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1198    N-[1-(4-fluorophenyl)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1199    N-[2-(3-fluorophenyl)ethyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1200    2-({4-[(2-ethylpyrrolidin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1201    N-(3-methylbutyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1202    2-({4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1203    N-[2-(diethylamino)ethyl]-N-ethyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1204    N-[2-(dimethylamino)ethyl]-N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1205    N-cyclopentyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1206    N-(4-methoxybenzyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1207    2-({4-[(4-methylpiperidin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1208    (2S)-1-({4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}sulfonyl)pyrrolidine-2-carboxamide-   I-1209    2-{[4-(piperidin-1-ylsulfonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1210    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzenesulfonamide-   I-1211    2-[(4-{[3-(diethylamino)pyrrolidin-1-yl]sulfonyl}phenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1212    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(2-thienyl)ethyl]benzenesulfonamide-   I-1213    N-[3-(dimethylamino)propyl]-N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1214    N-(4-chlorobenzyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1215    2-({4-[(3-oxopiperazin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1216    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(tetrahydrofuran-2-ylmethyl)benzenesulfonamide-   I-1217    N-methyl-N-(1-methylpyrrolidin-3-yl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1218    N-[(1R)-2,3-dihydro-1H-inden-1-yl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1219    2-{[4-(azetidin-1-ylsulfonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1220    N-methyl-N-[1-({4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}sulfonyl)pyrrolidin-3-yl]acetamide-   I-221    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-phenoxyethyl)benzenesulfonamide-   I-222    2-({4-[(4-ethylpiperazin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1223    N-cyclohexyl-N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1224    N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1225    4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-piperidin-1-ylethyl)benzenesulfonamide-   I-1226    2-({4-[(2-methylpyrrolidin-1-yl)sulfonyl]phenyl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1227    N-(2-isopropoxyethyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1228    N-ethyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyridin-4-ylmethyl)benzenesulfonamide-   I-1229    N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-pyridin-2-ylethyl)benzenesulfonamide-   I-1230    2-{[2-(1H-pyrrol-1-yl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1231    2-{-[(6-fluoro-4H-1,3-benzodioxin-8-yl)methyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1232    2-{[2-(2-chlorophenyl)-2-(dimethylamino)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1233    2-{[2-(4-methylpiperazin-1-yl)-1-phenylethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1234    2-{[(1-piperidin-1-ylcyclohexyl)methyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1235    2-{[(5-methyl-3-phenylisoxazol-4-yl)methyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-236    2-{[2-(2-methoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1237    2-{[2-(4-ethoxy-3-methoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1238    2-[(3,4-dimethylisoxazol-5-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1239    2-[(3-oxo-1,3-dihydro-2-benzofuran-5-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1240    2-[(1-phenyl-2-pyrrolidin-1-ylethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1241    2-{[2-(4-methoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1242    2-[(1-benzylpyrrolidin-3-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1243    2-{[5-fluoro-2-(1H-imidazol-1-yl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1244    2-[(pyridin-3-ylmethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1245    2-[(2-methyl-1,3-benzothiazol-6-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1246    2-[(4-methoxyphenyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1247    2-[(9-ethyl-9H-carbazol-3-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1248    2-[(2-aminoethyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1249    2-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1250    2-{[2-(2,4-difluorophenoxy)pyridin-3-yl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1251    2-[(1-benzylpiperidin-4-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1252    N,N,4-trimethyl-3-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1253    2-{[2-(4-benzylpiperazin-1-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1254    2-{[3-(4-bromo-1-methyl-1H-pyrazol-3-yl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1255    2-[(2-methyl-2-morpholin-4-ylpropyl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1256    2-{[2-(2,5-dimethoxyphenyl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1257    2-({6-[3-(trifluoromethyl)phenoxy]pyridin-3-yl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1258    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-methyl-1-phenylbutyl)benzamide-   I-1259    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[1-(4-hydroxyphenyl)ethyl]benzamide-   I-1260    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1-methyl-1-phenylethyl)benzamide-   I-1261    4-[(9-iodo-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1-methyl-1-phenylethyl)benzamide-   I-1262    N-[1-(4-fluorophenyl)ethyl]-4-[(9-iodo-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-1263    4-[(9-iodo-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1-phenylethyl)benzamide-   I-1264    N-methyl-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-prop-2-yn-1-ylbenzenesulfonamide-   I-1265    9-chloro-2-{[4-(morpholin-4-ylsulfonyl)phenyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one-   I-1266    N-(2-methoxyethyl)-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1267    N-[(5-methyl-2-furyl)methyl]-4-[(6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonamide-   I-1268    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzenesulfonic    acid-   I-1269    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[2-(dimethylamino)-1-phenylethyl]benzamide-   I-1270    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(1-phenyl-2-pyrrolidin-1-ylethyl)benzamide-   I-1271    4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzoic    acid-   I-1272    4-({4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]phenyl}sulfonyl)-1,4-diazepane-1-carbaldehyde-   I-1273    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]benzenesulfonamide-   I-1274    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(2-isopropoxyethyl)benzenesulfonamide-   I-1275    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyridin-4-ylmethyl)benzenesulfonamide-   I-1276    N-(2,3-dihydro-1-benzofuran-5-ylmethyl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-1277    N-(1,3-dihydro-2-benzofuran-5-yl)-4-[(7-methyl-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]benzamide-   I-1278    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(pyridin-2-ylmethyl)benzenesulfonamide-   I-1279    4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-morpholin-4-ylpropyl)benzenesulfonamide    General Synthetic Methodology

The compounds of the present invention can be prepared by methods knownto one of ordinary skill in the art and/or by reference to the schemesshown below and the synthetic examples that follow. Exemplary syntheticroutes are set forth in Schemes 1-12 below, and in the Examples.

Scheme 1 above shows a general route for preparing compounds of formula(II-A). Those of ordinary skill in the art will recognize that compoundsof formula (I) wherein Ring A is other than phenyl can be prepared bythe same general route, beginning with appropriate starting materialsanalogous to i.

Methods for the synthesis of substituted amino benzoic acid methylesters such as formula i are known. As shown in Scheme 1, conversion ofi to the acylated amino benzoic acid methyl ester of formula ii can beaccomplished by coupling with the appropriately substituted acylchloride. Compound iii can be prepared from ii by cyclization with asuitable base, such as KOt-Bu. Decarboxylation of iii to provide iv canbe effected by microwave irradiation in DMF/H₂O, according to Method C.Alternatively, iii can be converted to iv by heating in DMSO/H₂O withNaCl (Method D) or without NaCl (Method E). Those skilled in the artwill appreciate that the lactam nitrogen of formula iv can be alkylatedusing a suitable base, such as Cs₂CO₃, and an alkyl halide as describedin Method W. Alternatively, iv can be arylated using aryl halidesthrough a CuI-mediated process.

Treatment of iv with N,N-dimethylformamide dimethyl acetal in refluxingTHF affords v, according to Method F. Alternatively, the reaction may beperformed by treatment of iv with N,N-dimethylformamide dimethyl acetalin DMF followed by microwave irradiation, according to Method G. Enaminev is converted to the pyrimido compound vi by treatment with an aryl oralkyl guanidine. The reaction may be performed in the presence of a mildbase in ethanol or DMF utilizing heat or microwave irradiation,according to Method H and Method I.

As an alternative procedure to using guanidines to provide compounds offormula (II-A), a leaving group, such as a sulfone, can be directlydisplaced by alkyl and aryl amines. As shown in Scheme 2, treatment of vwith 2-methylisothiourea using Method I, provides compounds of formulavii. Treatment of vii with an oxidizing agent, such as MCPBA, providesthe sulfone viii. Compounds of formula viii can then be reacted withsubstituted amines or anilines in the presence of AlMe₃ to providecompounds of formula vi (Method J). The conversion of compounds viii tovi (formula (I)) is amenable to solution phase library synthesis.

Compounds of formula vi where Ring A is substituted with a halogen, suchas iodide, can be converted to a variety of compounds exemplifiedthrough formulae ix-xvii in Scheme 3. Thus, Stille coupling of vi-a withan allyl halide according to Method L provides compounds of formula ix,which can be converted to the aldehyde x through standardoxidation/cleavage conditions. Substituted amines of formula xi areobtained from x through reductive amination. Those skilled in the artwill appreciate that the aldehyde x can be oxidized using a suitablereagent to provide the acid, which can be further elaborated to providealternate substitutions, such as esters or amides. Aldehyde x can alsobe reduced using a suitable reagent to provide the alcohol, which can befurther elaborated to provide alternate substitutions, such as ethers ornitrites.

Alternatively, compounds of formula vi-a can be converted to xii througha palladium-mediated process outlined in Method M. The xii acid can befurther elaborated to the amides xiii according to Method N using astandard coupling reagent, such as TBTU, and the desired amine. Thoseskilled in the art will appreciate that the acid xii can be converted tothe ester and/or reduced using a suitable reagent to provide thealcohol, which can be further elaborated to provide alternatesubstitutions, such as ethers or nitrites. The alcohol could then beoxidized to the aldehyde, which could undergo reductive amination with avariety of substituted amines.

Compounds of formula vi-a readily undergo Sonogashira reactions withsubstituted acetylenes according to Method O to provide compounds offormula xiv. When treated with a suitable reducing agent, such as Pd/Caccording to Method P, compounds xiv are converted to compounds offormula xv. One skilled in the art will recognize that R^(#) canrepresent a variety of groups, including H and substituted alkyls, suchas —CH₂N(R⁺)₂, and —CH₂OH. The compounds xiv and xv, derived fromreaction of vi with propargyl alcohol, can be oxidized using a suitablereagent to the acid, which can be further elaborated to amides oresters. Alternatively, the alcohol can be oxidized using a suitablereagent to the aldehyde, which can undergo reductive amination toprovide substituted amines.

Lastly, compounds of formula vi can be converted to thecyano-substituted compound xvi according to Method Q. Using a suitablereducing agent, such as Raney nickel according to Method R, compounds offormula xvii are prepared from xvi.

The guanidines used for the preparation of compounds of formula xix areeither commercially available, or they can be prepared through theliterature methods described in Scheme 4 (Methods S or T or U).

Compounds of formula xx (Scheme 5) can be prepared from v usingguanidines xix wherein R^(a) is an aryl iodide. In methods analogous tothose described above for Scheme 3, a Sonogashira reaction withsubstituted acetylenes provides compounds of formula xxi. Using asuitable reducing agent, such as Pd/C, converts xxi to the saturatedcompounds xxii. One skilled in the art will recognize that R^(#) canrepresent a variety of groups, including H and substituted alkyls, suchas —CH₂N(R⁺)₂, and —CH₂OH. The compounds xxi and xxii, derived fromreaction of xx with propargyl alcohol, can be oxidized using a suitablereagent to the acid, which can be further elaborated to amides oresters. Alternatively, the alcohol can be oxidized using a suitablereagent to the aldehyde, which can undergo reductive amination toprovide substituted amines.

Compounds of formula xxiii (Scheme 6) can be prepared from v accordingto the method depicted in Scheme 1, using guanidines xix, where R^(a) isa phenyl group substituted with the appropriate alcohol. From thealcohols xxiii, aldehydes xxiv can be prepared using a suitableoxidizing agent, such as Dess-Martin periodinane. Compounds of formulaxxiv can be further elaborated to amines such as xxv through reductiveamination a suitable reducing agent, such as NaHB(OAc)₃. Additionally,alcohols xxiii can be converted to cyano compounds such as xxvi, whichcan be further elaborated to the amines xxvii using a suitable reducingagent, such as Raney nickel, as outlined in Method R.

Compounds of formula xxviii (Scheme 7) can be prepared from v accordingto methods depicted in Scheme 1, using guanidines xix, where R^(a) is aphenyl group substituted with the appropriate carboxylic acid. The acidscan be further elaborated to the amides xxix according to Method N usinga standard coupling reagent, such as TBTU, and the desired amine.

Thioamides of formula xxx (corresponding to Formula (II-D)) can beprepared from vi according to Scheme 8 using a suitable reagent, such asLawesson's Reagent. Similarly, the thioamides of Formulae (II-E) and(II-F) can be prepared from compounds of Formulae (II-B) and (II-C).

As outlined in Scheme 9, compounds of formula xxxv can be prepared fromxxxi using a 4-step sequence. Compound xxxi is converted to xxxii usinga suitable chlorinating agent, such as POCl₃. The dichloro pyrimidine isthen coupled with the appropriately substituted aniline using apalladium-catalyzed procedure to provide xxxiii. The ester xxxiii can behydrolyzed and coupled to the aniline using a suitable reagent, such asAcOH, to provide the lactam xxxiv. Finally, chloro pyrimidine xxxiv canbe displaced with the appropriately substituted amine or aniline toprovide compounds of formula xxxv.

As outlined in Scheme 10, compounds of formula xxxix can be preparedfrom xxxvi using a 3-step sequence. The dichloro pyrimidine xxxvi iscoupled with the appropriately substituted aniline using apalladium-catalyzed procedure to provide xxxvii. Subsequently, thechloro pyrimidine xxxvii can be displaced with the appropriatelysubstituted amine to provide cyano compound xxxviii, which can behydrolyzed and coupled to the aniline using a suitable reagent, such asNaOH, to provide the lactam xxxix.

Preparation of compounds of formula (II-B), wherein Y² is CRC, isachieved as shown in Scheme 11. The keto-intermediate iv undergoesα-bromination followed by conversion to the nitrile xli. Subsequenttreatment with an appropriate methylating agent, such as diazomethane,provides enol ether xlii, which when condensed with substitutedguanidines results in the 4-amino-substituted compound xliii. Oneskilled in the art will recognize that compounds of formula xliii can befurther elaborated to the substituted amines or amides. Compound xliiican also be converted to the iodide xliv. Those skilled in the art willappreciate that the iodide xliv can undergo a variety oftransformations, including the Sonogashira reactions mentioned above, aswell as other palladium couplings.

As outlined in Scheme 12, compounds of formula xlv can be prepared fromcompound vi-a by palladium-mediated coupling with an amine.

Uses, Formulation, and Administration

As discussed above, the present invention provides compounds that areinhibitors of protein kinases. The compounds can be assayed in vitro orin vivo for their ability to bind to and/or inhibit a protein kinase. Invitro assays include assays to determine inhibition of the ability ofthe kinase to phosphorylate a substrate protein or peptide. Alternate invitro assays quantitate the ability of the compound to bind to thekinase. Inhibitor binding may be measured by radiolabelling theinhibitor prior to binding, isolating the inhibitor/kinase complex anddetermining the amount of radiolabel bound. Alternatively, inhibitorbinding may be determined by running a competition experiment in whichnew inhibitors are incubated with the kinase bound to a knownradioligand. The compounds also can be assayed for their ability toaffect cellular or physiological functions mediated by protein kinaseactivity. Assays for each of these activities are described in theExamples and/or are known in the art. Nonlimiting examples of proteinkinases that are inhibited by the compounds of the invention includeChk-1, Aurora kinase, PLK, Chk-2, LCK, CDK1, CDK2E, PKA. In someembodiments, the compound of formula (I) inhibits a protein kinaseselected from the group consisting of Chk-1, Aurora kinase, and PLK.

In another aspect, therefore, the invention provides a method forinhibiting protein kinase activity in a cell, comprising contacting acell in which inhibition of a protein kinase is desired with a compoundof formula (I). In some embodiments, the compound of formula (I)interacts with and reduces the activity of more than one protein kinaseenzyme in the cell. By way of example, when assayed against Chk-1,Aurora kinase, and PLK, some compounds of formula (I) show inhibition ofall three enzymes.

In some embodiments, the compound of formula (I) is selective, i.e., theconcentration of the compound that is required for inhibition of one orseveral protein kinase enzymes is lower, preferably at least 2-fold,5-fold, 10-fold, or 50-fold lower, than the concentration of thecompound required for inhibition of other protein kinase enzymes. Insome such embodiments, the compound of formula (I) inhibits one or twoof Chk-1, Aurora kinase, and PLK at a concentration that is lower thanthat required for inhibition of the other enzyme(s).

In some embodiments, the compound of formula (I) inhibits one or moreprotein kinase enzymes involved in cell cycle regulation or celldivision. The invention thus provides a method for inhibiting cellproliferation, comprising contacting a cell in which such inhibition isdesired with a compound of formula (I). The phrase “inhibiting cellproliferation” is used to denote the ability of a compound of formula(I) to inhibit cell number or cell growth in contacted cells as comparedto cells not contacted with the inhibitor. An assessment of cellproliferation can be made by counting cells using a cell counter or byan assay of cell viability, e.g., an MTT or WST assay. Where the cellsare in a solid growth (e.g., a solid tumor or organ), such an assessmentof cell proliferation can be made by measuring the growth, e.g., withcalipers, and comparing the size of the growth of contacted cells withnon-contacted cells.

Preferably, the growth of cells contacted with the inhibitor is retardedby at least about 50% as compared to growth of non-contacted cells. Invarious embodiments, cell proliferation of contacted cells is inhibitedby at least about 75%, at least about 90%, or at least about 95% ascompared to non-contacted cells. In some embodiments, the phrase“inhibiting cell proliferation” includes a reduction in the number ofcontacted cells, as compare to non-contacted cells. Thus, a kinaseinhibitor that inhibits cell proliferation in a contacted cell mayinduce the contacted cell to undergo growth retardation, to undergogrowth arrest, to undergo programmed cell death (i.e., apoptosis), or toundergo necrotic cell death.

In another aspect, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) as defined above, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

If pharmaceutically acceptable salts of the compounds of the inventionare utilized in these compositions, the salts preferably are derivedfrom inorganic or organic acids and bases. For reviews of suitablesalts, see, e.g., Berge et al, J. Pharm. Sci. 66:1-19 (1977) andRemington: The Science and Practice of Pharmacy, 20th Ed., ed. A.Gennaro, Lippincott Williams & Wilkins, 2000.

Nonlimiting examples of suitable acid addition salts include thefollowing: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, lucoheptanoate, glycerophosphate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenyl-propionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate and undecanoate.

Suitable base addition salts include, without limitation, ammoniumsalts, alkali metal salts, such as sodium and potassium salts, alkalineearth metal salts, such as calcium and magnesium salts, salts withorganic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine,and salts with amino acids such as arginine, lysine, and so forth.

Also, basic nitrogen-containing groups may be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates, such as dimethyl,diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkylhalides, such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

The term “pharmaceutically acceptable carrier” is used herein to referto a material that is compatible with a recipient subject, preferably amammal, more preferably a human, and is suitable for delivering anactive agent to the target site without terminating the activity of theagent. The toxicity or adverse effects, if any, associated with thecarrier preferably are commensurate with a reasonable risk/benefit ratiofor the intended use of the active agent.

The pharmaceutical compositions of the invention can be manufactured bymethods well known in the art such as conventional granulating, mixing,dissolving, encapsulating, lyophilizing, or emulsifying processes, amongothers. Compositions may be produced in various forms, includinggranules, precipitates, or particulates, powders, including freezedried, rotary dried or spray dried powders, amorphous powders, tablets,capsules, syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions. Formulations may optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these.

Pharmaceutical formulations may be prepared as liquid suspensions orsolutions using a liquid, such as, but not limited to, an oil, water, analcohol, and combinations of these. Pharmaceutically suitablesurfactants, suspending agents, or emulsifying agents, may be added fororal or parenteral administration. Suspensions may include oils, such asbut not limited to, peanut oil, sesame oil, cottonseed oil, corn oil andolive oil. Suspension preparation may also contain esters of fatty acidssuch as ethyl oleate, isopropyl myristate, fatty acid glycerides andacetylated fatty acid glycerides. Suspension formulations may includealcohols, such as, but not limited to, ethanol, isopropyl alcohol,hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as butnot limited to, poly(ethyleneglycol), petroleum hydrocarbons such asmineral oil and petrolatum; and water may also be used in suspensionformulations.

Pharmaceutically acceptable carriers that may be used in thesecompositions include, but are not limited to, ion exchangers, alumina,aluminum stearate, lecithin, serum proteins, such as human serumalbumin, buffer substances such as phosphates, glycine, sorbic acid,potassium sorbate, partial glyceride mixtures of saturated vegetablefatty acids, water, salts or electrolytes, such as protamine sulfate,disodium hydrogen phosphate, potassium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

According to a preferred embodiment, the compositions of this inventionare formulated for pharmaceutical administration to a mammal, preferablya human being. Such pharmaceutical compositions of the present inventionmay be administered orally, parenterally, by inhalation spray,topically, rectally, nasally, buccally, vaginally or via an implantedreservoir. The term “parenteral” as used herein includes subcutaneous,intravenous, intramuscular, intra-articular, intra-synovial,intrasternal, intrathecal, intrahepatic, intralesional and intracranialinjection or infusion techniques. Preferably, the compositions areadministered orally, intravenously, or subcutaneously. The formulationsof the invention may be designed to be short-acting, fast-releasing, orlong-acting. Still further, compounds can be administered in a localrather than systemic means, such as administration (e.g., by injection)at a tumor site.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such ascarboxymethyl cellulose or similar dispersing agents which are commonlyused in the formulation of pharmaceutically acceptable dosage formsincluding emulsions and suspensions. Other commonly used surfactants,such as Tweens, Spans and other emulsifying agents or bioavailabilityenhancers which are commonly used in the manufacture of pharmaceuticallyacceptable solid, liquid, or other dosage forms may also be used for thepurposes of formulation. Compounds may be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection may be in ampoules or inmulti-dose containers.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers that are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried cornstarch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These may be prepared by mixing the agent with a suitable non-irritatingexcipient which is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract may be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used. For topicalapplications, the pharmaceutical compositions may be formulated in asuitable ointment containing the active component suspended or dissolvedin one or more carriers. Carriers for topical administration of thecompounds of this invention include, but are not limited to, mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical compositions may be formulated in asuitable lotion or cream containing the active components suspended ordissolved in one or more pharmaceutically acceptable carriers. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith our without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The pharmaceutical compositions of the invention preferably areformulated for administration to a patient having, or at risk ofdeveloping or experiencing a recurrence of, a protein kinase-mediateddisorder. The term “patient”, as used herein, means an animal,preferably a mammal, more preferably a human. Preferred pharmaceuticalcompositions of the invention are those formulated for oral,intravenous, or subcutaneous administration. However, any of the abovedosage forms containing a therapeutically effective amount of a compoundof the invention are well within the bounds of routine experimentationand therefore, well within the scope of the instant invention. In someembodiments, the pharmaceutical composition of the invention may furthercomprise another therapeutic agent. In some embodiments, such othertherapeutic agent is one that is normally administered to patients withthe disease or condition being treated.

By “therapeutically effective amount” is meant an amount sufficient tocause a detectable decrease in protein kinase activity or the severityof a protein kinase-mediated disorder. The amount of protein kinaseinhibitor needed will depend on the effectiveness of the inhibitor forthe given cell type and the length of time required to treat thedisorder. It should also be understood that a specific dosage andtreatment regimen for any particular patient will depend upon a varietyof factors, including the activity of the specific compound employed,the age, body weight, general health, sex, and diet of the patient, timeof administration, rate of excretion, drug combinations, the judgment ofthe treating physician, and the severity of the particular disease beingtreated. The amount of additional therapeutic agent present in acomposition of this invention typically will be no more than the amountthat would normally be administered in a composition comprising thattherapeutic agent as the only active agent. Preferably, the amount ofadditional therapeutic agent will range from about 50% to about 100% ofthe amount normally present in a composition comprising that agent asthe only therapeutically active agent.

In another aspect, the invention provides a method for treating apatient having, or at risk of developing or experiencing a recurrenceof, a protein kinase-mediated disorder. As used herein, the term“protein kinase-mediated disorder” includes any disorder, disease orcondition which is caused or characterized by an increase in kinaseexpression or activity, or which requires kinase activity. The term“protein kinase-mediated disorder” also includes any disorder, diseaseor condition in which inhibition of protein kinase activity isbeneficial. In some embodiments, the protein kinase-mediated disorder isone in which inhibition of Chk-1, Aurora kinase, or PLK activity isbeneficial.

The protein kinase inhibitors of the invention can be used to achieve abeneficial therapeutic or prophylactic effect, for example, in subjectswith a proliferative disorder. Non-limiting examples of proliferativedisorders include chronic inflammatory proliferative disorders, e.g.,psoriasis and rheumatoid arthritis; proliferative ocular disorders,e.g., diabetic retinopathy; benign proliferative disorders, e.g.,hemangiomas; and cancer. As used herein, the term “cancer” refers to acellular disorder characterized by uncontrolled or disregulated cellproliferation, decreased cellular differentiation, inappropriate abilityto invade surrounding tissue, and/or ability to establish new growth atectopic sites. The term “cancer” includes, but is not limited to, solidtumors and bloodborne tumors. The term “cancer” encompasses diseases ofskin, tissues, organs, bone, cartilage, blood, and vessels. The term“cancer” further encompasses primary and metastatic cancers.

Non-limiting examples of solid tumors that can be treated with thedisclosed protein kinase inhibitors include pancreatic cancer; bladdercancer; colorectal cancer; breast cancer, including metastatic breastcancer; prostate cancer, including androgen-dependent andandrogen-independent prostate cancer; renal cancer, including, e.g.,metastatic renal cell carcinoma; hepatocellular cancer; lung cancer,including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolarcarcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer,including, e.g., progressive epithelial or primary peritoneal cancer;cervical cancer; gastric cancer; esophageal cancer; head and neckcancer, including, e.g., squamous cell carcinoma of the head and neck;melanoma; neuroendocrine cancer, including metastatic neuroendocrinetumors; brain tumors, including, e.g., glioma, anaplasticoligodendroglioma, adult glioblastoma multiforme, and adult anaplasticastrocytoma; bone cancer; and soft tissue sarcoma.

Non-limiting examples of hematologic malignancies that can be treatedwith the disclosed protein kinase inhibitors include acute myeloidleukemia (A ML); chronic myelogenous leukemia (C ML), includingaccelerated C ML and C ML blast phase (C ML-BP); acute lymphoblasticleukemia (ALL); chronic lymphocytic leukemia (CLL); Hodgkin's disease(HD); non-Hodgkin's lymphoma (NHL), including follicular lymphoma andmantle cell lymphoma; B-cell lymphoma; T-cell lymphoma; multiple myeloma(MM); Waldenstrom's macroglobulinemia; myelodysplastic syndromes (MDS),including refractory anemia (RA), refractory anemia with ringedsiderblasts (RARS), (refractory anemia with excess blasts (RAEB), andRAEB in transformation (RAEB-T); and myeloproliferative syndromes.

The compounds of formula (I) are particularly useful in the treatment ofcancers or cell types in which protein kinase activity is upregulated.The compounds of the invention are especially useful in the treatment ofcancers or cell types in which Chk-1, Aurora, or PLK activity isupregulated, including, in particular, rapidly proliferating cells.Chk-1 also is upregulated in drug-resistant cells (Shyjan et al., U.S.Pat. No. 6,723,498 (2004)), as well as retinoblastomas such as Rbnegative or inactivated cells (Gottifredi et al., Mol. Cell. Biol.,21:1066 (2001)), or cells in which the ARF^(p14/p19) locus has beeninactivated or misregulated. The disclosed Chk-1 inhibitors also areparticularly useful in the treatment of cancers or cell types in whichanother checkpoint pathway has been mutated or abrogated, including,without limitation, cancers or cell types in which p53 or the p53pathway has been inactivated or abrogated.

In some embodiments, the compound or composition of the invention isused to treat a patient having or at risk of developing or experiencinga recurrence in a cancer selected from the group consisting ofcolorectal cancer, ovarian cancer, breast cancer, gastric cancer,prostate cancer, and pancreatic cancer. In certain embodiments, thecancer is selected from the group consisting of breast cancer,colorectal cancer, and pancreatic cancer.

In some embodiments, the protein kinase inhibitor of the invention isadministered in conjunction with another therapeutic agent. The othertherapeutic agent may inhibit the same or a different protein kinase, ormay operate by a different mechanism. In some embodiments, the othertherapeutic agent is one that is normally administered to patients withthe disease or condition being treated. The protein kinase inhibitor ofthe invention may be administered with the other therapeutic agent in asingle dosage form or as a separate dosage form. When administered as aseparate dosage form, the other therapeutic agent may be administeredprior to, at the same time as, or following administration of theprotein kinase inhibitor of the invention.

In some embodiments, a protein kinase inhibitor of formula (I) isadministered in conjunction with an anticancer agent. As used herein,the term “anticancer agent” refers to any agent that is administered toa subject with cancer for purposes of treating the cancer. Nonlimitingexamples anticancer agents include: radiotherapy; immunotherapy; DNAdamaging chemotherapeutic agents; and chemotherapeutic agents thatdisrupt cell replication.

Non-limiting examples of DNA damaging chemotherapeutic agents includetopoisomerase I inhibitors (e.g., irinotecan, topotecan, camptothecinand analogs or metabolites thereof, and doxorubicin); topoisomerase IIinhibitors (e.g., etoposide, teniposide, and daunorubicin); alkylatingagents (e.g., melphalan, chlorambucil, busulfan, thiotepa, ifosfamide,carmustine, lomustine, semustine, streptozocin, decarbazine,methotrexate, mitomycin C, and cyclophosphamide); DNA intercalators(e.g., cisplatin, oxaliplatin, and carboplatin); DNA intercalators andfree radical generators such as bleomycin; and nucleoside mimetics(e.g., 5-fluorouracil, capecitibine, gemcitabine, fludarabine,cytarabine, mercaptopurine, thioguanine, pentostatin, and hydroxyurea).

Chemotherapeutic agents that disrupt cell replication include:paclitaxel, docetaxel, and related analogs; vincristine, vinblastin, andrelated analogs; thalidomide and related analogs (e.g., CC-5013 andCC-4047); protein tyrosine kinase inhibitors (e.g., imatinib mesylateand gefitinib); proteasome inhibitors (e.g., bortezornib); NF-κBinhibitors, including inhibitors of IκB kinase; antibodies which bind toproteins overexpressed in cancers and thereby downregulate cellreplication (e.g., trastuzumab, rituximab, cetuximab, and bevacizumab);and other inhibitors of proteins or enzymes known to be upregulated,over-expressed or activated in cancers, the inhibition of whichdownregulates cell replication.

In some embodiments, a compound of formula (I) that inhibits Chk-1 isused in combination with radiation therapy or a chemotherapeutic agentthat acts by causing damage to the genetic material of cells(collectively referred to herein as “DNA damaging agents”). In someembodiments, the combination of a Chk-1 inhibitor of formula (I) with aDNA damaging agent is used to treat a subject with a multi-drugresistant cancer. A cancer is resistant to a drug when it resumes anormal rate of tumor growth while undergoing treatment with the drugafter the tumor had initially responded to the drug. A tumor “respondsto a drug” when it exhibits a decrease in tumor mass or a decrease inthe rate of tumor growth. The term “multi-drug resistant cancer” refersto cancer that is resistant to two or more drugs, often as many as fiveor more.

When used in combination with a DNA damaging agent, an “effectiveamount” of a Chk-1 inhibitor is the quantity of the inhibitor at which agreater response is achieved when the Chk-1 inhibitor is co-administeredwith the DNA damaging anti-cancer drug and/or radiation therapy than isachieved when the DNA damaging anti-cancer drug and/or radiation therapyis administered alone.

In order that this invention be more fully understood, the followingpreparative and testing examples are set forth. These examplesillustrate how to make or test specific compounds, and are not to beconstrued as limiting the scope of the invention in any way.

EXAMPLES Definitions

-   AcOH acetic acid-   ATP adenosine triphosphate-   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   Boc tert-butoxycarbonyl-   BSA bovine serum albumin-   DMAP 4-dimethylaminopyridine-   DMF dimethylformamide-   DMF-DMA dimethylformamide dimethylacetal-   DMSO dimethylsulfoxide-   DTT dithiothreitol-   EDTA ethylenediaminetetraacetic acid-   EtOAc ethyl acetate-   EtOH ethanol-   MCPBA meta-chloroperbenzoic acid-   MeOH methanol-   MTT methylthiazoletetrazolium-   WST    (4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene    disulfonate sodium salt)-   PKA cAMP-dependent protein kinase-   tBu tert-butyl-   THF tetrahydrofuran-   TBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   h hours-   min minutes-   m/z mass to charge-   MS mass spectrum-   RP LC-MS reverse phase liquid chromatography-mass spectrometry-   HRMS high resolution mass spectrum

Compounds I-1 to I-93 and I-135 to I-1279 in Table 1 were prepared bymethods generally analogous to those described in Schemes I-12 above andExamples 1-24 below. Mass spectra matched calculated values.

HRMS data were collected on a Sciex Qstar time of flight massspectrometer coupled to an Agilent HPLC. Experimentally determined(M+H)⁺ were within 10 ppm error of calculated (M+H)⁺.

LCMS conditions: spectra were run on a Phenominex Luna 5 μm C18 50×4.6mm column on a Hewlett-Packard HP1100 at 2.5 mL/min for a 3 minute runusing the following gradients:

Method Formic Acid (FA): Acetonitrile containing zero to 100 percent0.1% formic acid in water.

Method Ammonium Acetate (AA): Acetonitrile containing zero to 100percent 10 mM ammonium acetate in water.

Example 1 Representative Synthesis of Compounds of Formula i (See Scheme1)

5-Iodo-2-methyl-phenylamine (b)

To a solution of 4-iodo-1-methyl-2-nitro-benzene (25.0 g, 107 mmol) in300 mL of ethanol was added sulfided platinum (3.00 g) and ammoniumformate (20.3 g, 321 mmol). The mixture was heated to reflux for 12 hand then cooled to 22° C., filtered through Celite® and concentrated invacuo. The resulting residue was diluted with H₂O (300 mL) and extractedwith 3×200 mL CH₂Cl₂. The organic fractions were combined, washed withbrine, dried over Na₂SO₄ and concentrated in vacuo to give b (21.1 g,95%): MS m/z=234 (M+H).

N-(5-Iodo-2-methyl-phenyl)-acetamide (c)

A solution of 5-iodo-2-methyl-phenylamine (20.4 g, 87.6 mmol) in 200 mLof dry CH₂Cl₂ was cooled to 0° C. and acetic anhydride (16.5 mL, 175mmol) was added dropwise. The mixture was heated to 50° C. for 2 h andthen cooled to 22° C. The resulting white precipitate was filtered togive c (18.4 g, 76%): MS m/z=276 (M+H).

2-Acetylamino-4-iodo-benzoic acid (d)

To a suspension of N-(5-iodo-2-methyl-phenyl)-acetamide (18.9 g, 68.9mmol) in 200 mL H₂O was added magnesium sulfate (10.8 g, 89.7 mmol). Themixture was heated to 100° C., and potassium permanganate (32.7 g, 206mmol) was added. After 1 h, an additional portion of potassiumpermanganate (10.9 g, 68.9 mmol) was added. Again after 1 h, a finalportion of potassium permanganate (10.9 g, 68.9 mmol) was added and thereaction was stirred 12 h. The mixture was then cooled to 22° C. andfiltered through a pad of Celite®. The filtrate was acidified with 1 NHCl, and the resulting white precipitate was filtered to give d (14.8 g,70%): MS m/z=304 (M−H).

2-Amino-4-iodo-benzoic acid methyl ester (i-b)

To 2-acetylamino-4-iodo-benzoic acid (13.8 g, 45.3 mmol) in 200 mL ofdry methanol was added SOCl₂ (32.7 mL, 453 mmol) dropwise at 0° C. Thereaction mixture was then heated at 65° C. for 2 h. The reaction wasthen cooled to 0° C., an additional portion of SOCl₂ (10 mL, 137 mmol)was added, and the reaction was heated at 65° C. for 2 h. The reactionwas then cooled to 0° C., a final portion of SOCl₂ (10 mL, 137 mmol) wasadded, and the reaction was heated at 65° C. for 48 h. The reaction wasthen cooled to 22° C. and concentrated in vacuo. The resulting residuewas diluted with H₂O and extracted with 3×150 mL CH₂Cl₂. The combinedorganic fractions were washed with brine and dried over Na₂SO₄ to givei-b (11.7 g, 93%): MS m/z=278 (M+H).

Methyl 2-amino-5-methoxybenzoate (i-e)

Hydrogen chloride gas was bubbled through a solution of2-amino-5-methoxybenzoic acid (5.0 g, 30 mmol) in MeOH (200 mL) for 30minutes. The solution was heated at 60° C. overnight. The reaction wascooled and the solvent removed in vacuo. The residue was dissolved inwater, basified with 5M NaOH and extracted twice with ether. The etherextracts were washed with 5M NaOH and water, dried (MgSO₄), filtered andconcentrated in vacuo to give i-e (4.25 g, 78%): MS m/z=182 (M+H).

Methyl 2-amino-5-fluorobenzoate (i-f)

In a manner similar to that described above for methyl2-amino-5-methoxybenzoate, 7.82 g of 2-amino-5-fluorobenzoic acid wasconverted to i-f (40%): MS m/z=170 (M+H).

Methyl 2-amino-4-methylbenzoate (i-g)

In a manner similar to that described above for methyl2-amino-5-methoxybenzoate, 1.90 g of 2-amino-4-methylbenzoic acid wasconverted to i-g (94%): MS m/z=166 (M+H).

Esters i-a, i-c, i-d, i-i, i-j, and i-k are commercially available.Ester i-h was not prepared; ii-h was prepared as described below.

Example 2 Method A for the Synthesis of Compounds of Formula ii (SeeScheme 1)

2-(3-Ethoxycarbonyl-propionylamino)-5-iodo-benzoic acid methyl ester(ii-a)

To methyl 2-amino-5-iodobenzoate (i-a) (15 g, 54 mmol) was added 200 mLof CH₂Cl₂, followed by DIEA (9.4 mL, 54 mmol) and a catalytic amount ofDMAP. Ethyl 4-chloro-4-oxobutanoate (R^(c)═R^(d)═H) (8.5 mL, 60 mmol)was added, and the reaction mixture was allowed to stir at roomtemperature overnight. The reaction mixture was then poured into 250 mLH₂O, and the organic layer was washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo to afford ii-a (22 g, 99%) as a paleyellow solid: MS m/z=406 (M+H).

2-(3-Ethoxycarbonyl-propionylamino)-4-iodo-benzoic acid methyl ester(ii-b)

In a manner similar to that described for method A,2-amino-4-iodobenzoic acid methyl ester (i-b) was converted to ii-b(99%): MS m/z=406 (M+H).

2-(3-Ethoxycarbonyl-propionylamino)-benzoic acid methyl ester (ii-c)

In a manner similar to that described for method A, 2-amino-benzoic acidmethyl ester (i-c) was converted to ii-c (93%): MS m/z=280 (M+H).

5-Chloro-2-(3-ethoxycarbonyl-propionylamino)-benzoic acid methyl ester(ii-d)

In a manner similar to that described in method A,2-amino-5-chloro-benzoic acid methyl ester (i-d) was converted to ii-d(90%): MS m/z=314 (M+H).

Methyl 2-(4-ethoxy-4-oxobutanamido)-5-methoxybenzoate (ii-e)

In a manner similar to that described for method A, methyl2-amino-5-methoxybenzoate (i-e) was converted to ii-e (93%): MS m/z=310(M+H).

Methyl 2-(4-ethoxy-4-oxobutanamido)-5-fluorobenzoate (ii-f)

In a manner similar to that described for method A, methyl2-amino-5-fluorobenzoate (i-f) was converted to ii-f (95%): MS m/z=298(M+H).

Methyl 2-(4-ethoxy-4-oxobutanamido)-4-methylbenzoate (ii-g)

In a manner similar to that described for method A, methyl2-amino-4-methylbenzoate (i-g) was converted to ii-g (97%): MS m/z=294(M+H).

2-(4-Methoxy-4-oxobutanamido)nicotinic acid (ii-h-1)

In a manner similar to method A, 2-aminonicotinic acid was converted toii-h-1 (46%).

Methyl 2-(4-methoxy-4-oxobutanamido)nicotinate (ii-h)

2-(4-Methoxy-4-oxobutanamido)nicotinic acid (ii-h-1) (1.28 g, 4.8 mmol)was dissolved in an equimolar mixture of CH₂Cl₂ and methanol (20 mL) andcooled to 0° C. TMS diazomethane (2M solution in diethyl ether; 5.2 mL,10.6 mmol) was added dropwise. The mixture was stirred for 1 h andwarmed to 23° C. Volatiles were removed under reduced pressure toprovide ii-h as a pale yellow solid (1.37 g, 100%) MS m/z=267 (M+1).

4-Chloro-2-(3-methoxycarbonyl-2(R)-methyl-propionylamino)-benzoic acidmethyl ester (ii-i)

(R)-(+)-2-Methylsuccinic acid 4-methyl ester (1 g, 6.8 mmol) wasdissolved in CH₂Cl₂ (40 mL). Oxalyl chloride [2M in CH₂Cl₂ (3.7 mL, 7.4mmol)] was then added followed by a few drops of DMF (0.1 mL). Themixture was stirred at 22° C. for 3 h, after which it was concentratedunder reduced pressure. The resulting residue was then suspended inCH₂Cl₂ (10 mL) and added slowly to a stirring solution of methyl2-amino-4-chlorobenzoate (i-i) (1.26 g, 6.8 mmol) in triethylamine (3.76mL, 27.2 mmol) in CH₂Cl₂ (40 mL). The reaction mixture was allowed tostir at 22° C. for 1 h. The mixture was then partitioned between CH₂Cl₂(50 mL) and H₂O (50 mL). The aqueous layer was extracted with CH₂Cl₂(3×50 mL) and the combined organic layers were washed with brine, driedover MgSO₄, filtered and concentrated to dryness. The resulting orangeresidue was purified by column chromatography, eluting with 20% ethylacetate in hexane to give ii-i as a clear oil (1.8 g, 85% yield): MSm/z=314 (M+H).

4-Chloro-2-(3-ethoxycarbonyl-propionylamino)-benzoic acid methyl ester(ii-j)

In a manner similar to that described in method A,2-amino-5-chloro-benzoic acid methyl ester (i-j) was converted to ii-j(90%): MS m/z=314 (M+H).

5-Bromo-2-(3-ethoxycarbonyl-propionylamino)-benzoic acid methyl ester(ii-k)

In a manner similar to that described for method A,2-amino-5-bromo-benzoic acid methyl ester (i-k) was converted to ii-k(100%): MS m/z=358 (M+H), 360 (M+2H).

Example 3 Method B for the Synthesis of Compounds of Formula iii (SeeScheme 1)

7-Iodo-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acidethyl ester (iii-a)

To a solution of methyl 2-(4-ethoxy-4-oxobutanamido)-5-iodobenzoate(ii-a) (22.0 g, 54 mmol) in 125 mL of THF was added a 1 M solution ofKOt-Bu in THF (119 mL, 119 mmol). The reaction was complete after 2.5 hat 22° C. H₂O (250 mL) and 1N HCl (60 mL) were added to the solution,and the resulting precipitate was filtered, washed with 2×50 mL Et₂O,and dried in vacuo to give iii-a (16.1 g, 83%) as a whitish/gray solidas a mixture of ethyl and methyl esters: MS m/z=374 (M+H) and 360 (M+H).

8-Iodo-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acidethyl ester (iii-b)

In a manner similar to that described for method B,2-(3-ethoxycarbonyl-propionylamino)-4-iodo-benzoic acid methyl ester(ii-b) was converted to iii-b (89% yield mixture methyl and ethylesters): MS m/z=374 (M+H) and 360 (M+H).

2,5-Dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethylester (iii-c)

In a manner similar to that described in method B,2-(3-ethoxycarbonyl-propionylamino)-benzoic acid methyl ester (ii-c) wasconverted to iii-c (87%): MS m/z=248 (M+H).

7-Chloro-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylicacid ethyl ester (iii-d)

In a manner similar to that described in method B,5-chloro-2-(3-ethoxycarbonyl-propionylamino)-benzoic acid methyl ester(ii-d) was converted to iii-d (84%): MS m/z=282 (M+H).

7-Methoxy-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylicacid, mixture of methyl and ethyl esters (iii-e)

In a manner similar to that described for method B, methyl2-(4-ethoxy-4-oxobutanamido)-5-methoxybenzoate (ii-e) was converted toiii-e (59%, recrystallized from EtOH): MS m/z=264 and 278 (M+H).

7-Fluoro-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylicacid, mixture of methyl and ethyl esters (iii-f)

In a manner similar to that described for method B, methyl2-(4-ethoxy-4-oxobutanamido)-5-fluorobenzoate (ii-f) was converted toiii-f (57%, recrystallized from EtOH): MS m/z=252 and 266 (M+H).

8-Methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylicacid, mixture of methyl and ethyl esters (iii-g)

In a manner similar to that described for method B, methyl2-(4-ethoxy-4-oxobutanamido)-4-methylbenzoate (ii-g) was converted toiii-g (49%, recrystallized from EtOH): MS m/z=248 and 262 (M+H).

Methyl5,8-dioxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-6-carboxylate(iii-h)

In a manner similar to method B, methyl2-(4-methoxy-4-oxobutanamido)-nicotinate (ii-h) was converted to iii-h(47%): MS m/z=235 (M+H).

8-Chloro-3-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylicacid methyl ester (iii-i)

In a manner similar to that described for method B,4-chloro-2-(3-methoxycarbonyl-2-methyl-propionylamino)-benzoic acidmethyl ester (ii-i) was converted to iii-i (78%): MS m/z=282 (M+H).

8-Chloro-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylicacid methyl ester (iii-j)

In a manner similar to that described for method B,4-chloro-2-(3-ethoxycarbonyl-propionylamino)-benzoic acid methyl ester(ii-j) was converted to iii-j (81%): MS m/z=268 (M+H).

7-Bromo-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylicacid ethyl ester (iii-k)

In a manner similar to that described for method B,5-bromo-2-(3-ethoxycarbonyl-propionylamino)-benzoic acid methyl ester(ii-k) was converted to iii-k (60% yield mixture methyl and ethylesters): MS m/z=312 (M+H), 314 (M+2H) and 326 (M+H), 328 (M+2H).

Example 4 Method C for the Synthesis of Compounds of Formula iv (SeeScheme 1)

8-Chloro-3-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-i)

To a solution of8-chloro-3-methyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylicacid methyl ester (iii-i) (0.2 g, 0.7 mmol) in DMF (2 mL) was added H₂O(0.3 mL) and the reaction mixture heated to 230° C. in a microwavereactor for 5 minutes. H₂O (20 mL) was added to the reaction mixture andthe resulting precipitate was filtered and washed with H₂O. The solidwas dried under reduced pressure at 40° C. for 16 h to afford iv-i (0.12g, 77%) as a white solid: MS m/z=224 (M+H).

8-Iodo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-b)

In a manner similar to that described for method C,8-iodo-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acidethyl ester (iii-b) was converted to iv-b (69%): MS m/z=300 (M−H).

3,4-Dihydro-1H-benzo[b]azepine-2,5-dione (iv-c)

In a manner similar to that described for method C,2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylic acid ethylester (iii-c) was converted to iv-c (48%): MS m/z=174 (M−H).

7-Chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-d)

In a manner similar to that described for method C,7-chloro-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylicacid ethyl ester (iii-d) was converted to iv-d (29%): MS m/z=208 (M−H).

8-Chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-j)

In a manner similar to that described for method C,8-chloro-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylicacid methyl ester (iii-j) was converted to iv-j (80%): MS m/z=210 (M+H).

7-Bromo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-k)

In a manner similar to that described for method C,7-bromo-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylicacid ethyl ester (iii-k) was converted to iv-k (89%): MS m/z=254 (M+H),256 (M+2H).

Example 5 Method D for the Synthesis of Compounds of Formula iv (SeeScheme 1)

7-Iodo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-a)

To a solution of ethyl7-iodo-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-4-carboxylate(iii-a) (4.84 g, 13.2 mmol) in dimethyl sulfoxide (66 mL) was added asolution of NaCl (81 mg, 15.9 mmol) in H₂O (475 μL, 26.4 mmol). Thereaction mixture was heated to 150° C. for 2 h, and subsequently cooledto 0° C. for 30 min. H₂O (120 mL) was added and the solution was allowedto stir for an additional 1.5 h at 0° C. The resulting precipitate wasfiltered to provide iv-a (3.2 g, 81%) as a purple/brown solid: MSm/z=302 (M+H).

6,7-Dihydro-9H-pyrido[2,3-b]azepine-5,8-dione (iv-h)

In a manner similar to method D,methyl-5,8-dioxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine-6-carboxylate(iii-h) was converted to iv-h (50%): MS m/z=177 (M+H).

Example 6 Method E for the Synthesis of Compounds of Formula iv (SeeScheme 1)

8-Methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-g)

To a solution of iii-g (mixture of methyl and ethyl esters) (1.32 g,5.19 mmol) in DMSO (50 mL) was added H₂O (2.4 mL) and the resultingsolution was heated to 150° C. for 1 h. An additional portion of H₂O(2.4 mL) was added and the solution heated at 150° C. for 1 h. A thirdportion of H₂O (2.4 mL) was added and the solution heated at 150° C. for2 h. The reaction mixture was cooled to room temperature and dilutedwith H₂O (50 mL). The solution was extracted with CH₂Cl₂ (3×50 mL) andthe combined organics were washed with H₂O (2×50 mL). The organics weredried (MgSO₄), filtered and evaporated in vacuo to give the crudeproduct, which was recrystallized from ethanol to give pure iv-g (641mg, 65%) as a white powder.

7-Methoxy-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-e)

In a manner similar to that described for Method E, iii-e was convertedto iv-e (76%, recrystallized from EtOH): MS m/z=206 (M+H).

7-Fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-f)

In a manner similar to that described for Method E, iii-f was convertedto iv-f (62%, recrystallized from EtOH): MS m/z=194 (M+H).

Example 7 Method F for the Synthesis of Compounds of Formula v (SeeScheme 1)

4-Dimethylaminomethylene-7-iodo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-a)

To a solution of 7-iodo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-a)(1.67 g, 5.54 mmol) in THF (15 mL) was added dimethylformamidedimethylacetal (4.0 mL, 27.7 mmol) and the reaction mixture heated to70° C. for 1 h. The reaction mixture was cooled to 22° C., treated withEt₂O (50 mL), and the resulting precipitate filtered and dried in vacuoto give v-a (1.64 g, 83%) as a brown powder: MS m/z=357 (M+H).

4-Dimethylaminomethylene-8-iodo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-b)

In a manner similar to that described for method F,8-iodo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-b) was converted tov-b (66%): MS m/z=357 (M+H).

4-Dimethylaminomethylene-7-methoxy-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-e)

To a flask containing iv-e (1.9 g) was added DMF-DMA (15 mL) and themixture was heated to 110° C. for 1 h. The mixture was cooled to 0° C.,filtered, washed with ether and dried to give v-e (2.2 g, 91%): MSm/z=261 (M+H).

4-Dimethylaminomethylene-7-fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-f)

In a manner similar to that described above for4-dimethylamino-methylene-7-methoxy-3,4-dihydro-1H-benzo[b]azepine-2,5-dione,7-fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-f) was convertedto v-f (85%): MS m/z=249 (M+H).

4-Dimethylaminomethylene-8-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-g)

In a manner similar to that described above for4-dimethylamino-methylene-7-methoxy-3,4-dihydro-1H-benzo[b]azepine-2,5-dione,7-fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione, 0.64 g of8-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione was converted to v-g(87%): MS m/z=245 (M+H).

(Z)-6-Dimethylaminomethylene-6,7-dihydro-9H-pyrido[2,3-b]azepine-5,8-dione(v-h)

In a manner similar to method F (CH₂Cl₂ used in place of THF),6,7-dihydro-9H-pyrido[2,3-b]azepine-5,8-dione (iv-h) was converted tov-h (100%): MS m/z=232 (M+H).

7-Bromo-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-k)

In a manner similar to that described for method F,7-bromo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-k) was converted tov-k (63%): MS m/z=309 (M+H), 311 (M+2H).

8-Chloro-1-phenyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-l-1)

8-Chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-j) (500 mg, 2.4mmol) was combined with K₂CO₃ (660 mg, 4.8 mmol) under an atmosphere ofargon. Phenylbromide (370 mg, 2.4 mmol) andN,N′-Dimethyl-ethane-1,2-diamine (21 mg, 0.24 mmol, 10 mol %) wereadded, followed by 10 mL of toluene. The mixture was degassed with anargon sparge for 10 min. CuI (23 mg, 0.12 mmol, 5 mol %) was added andthe reaction was heated to 110° C. for 48 h. The mixture was filteredand volatiles removed in vacuo. Chromatographic purification providedthe desired product contaminated with 10%8-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (172 mg, 34%) MSm/z=286 (M+1).

8-Chloro-4-dimethylaminomethylene-1-phenyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-l)

In a manner similar to method F (toluene used in place of THF)8-chloro-1-phenyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-l-1) wasconverted to v-l: MS m/z=341 (M+H).

Example 8 Method G for the Synthesis of Compounds of Formula v (SeeScheme 1)

8-Chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j)

To a solution of iv-j (0.15 g, 0.72 mmol) in DMF (5 mL) was addeddimethylformamide dimethylacetal (0.11 mL, 0.79 mmol) and the reactionmixture heated at 200° C. for 100 s in the microwave. The reactionmixture was cooled to 22° C., treated with Et₂O (5 mL), and theresulting precipitate filtered and dried in vacuo to give v-j (0.062 g,33%) as a brown powder: MS m/z=265 (M+H).

4-Dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-c)

In a manner similar to that described for method G,3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-c) was converted to v-c(95%): MS m/z=231 (M+H).

7-Chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-d)

In a manner similar to that described for method G,7-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-d) was convertedto v-d (24%): MS m/z=265 (M+H).

8-Chloro-4-dimethylaminomethylene-3-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-i)

In a manner similar to that described for method G,8-chloro-3-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-i) wasconverted to v-i (100%): MS m/z=279 (M+H).

8-Chloro-4-dimethylaminomethylene-1-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-m)

In a manner similar to that described for method G,8-chloro-1-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-m-1,prepared by Method W, as described below) was converted to v-m (100%yield): MS m/z=279 (M+H).

1-Benzyl-8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-n)

In a manner similar to that described for method G,1-benzyl-8-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-n-1,prepared by Method W, as described below) was converted to v-n (100%):MS m/z=355 (M+H).

8-Chloro-4-dimethylaminomethylene-1,3-dimethyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-o)

In a manner similar to that described for method G,8-chloro-1,3-dimethyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (preparedfrom iv-i in a manner similar to that described for Method W below) wasconverted to v-o (100% yield): MS m/z=293 (M+H).

Example 9 Method W for Lactam Alkylation8-Chloro-1-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-m-1)

8-Chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-j) (0.2 g, 1 mmol)was dissolved in a mixture of THF (10 mL) and DMF (2 mL). Cesiumcarbonate (0.98 g, 3 mmol) and methyl iodide (0.069 mL, 1.1 mmol) wereadded and the reaction mixture was stirred at room temperature for 3 h.The mixture was concentrated under reduced pressure and dichloromethane(10 mL) was added. The inorganic precipitate was filtered and thefiltrate was concentrated under reduced pressure to give a viscousresidue. This residue was purified utilizing column chromatography,eluting with 50% ethyl acetate/hexane to afford the title compound as awhite solid (0.1 g, 45%): MS m/z=224 (M+H).

1-Benzyl-8-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-n-1)

In a manner similar to that described for Method W,8-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione and benzyl bromidewere converted to the title compound (38%): MS m/z=300 (M+H).

Example 10 Method H for the Synthesis of Compounds of Formula vi (SeeScheme 1)

2-(3,4-Dimethoxy-phenylamino)-10-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-26)

To a solution of4-dimethylaminomethylene-7-iodo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-a) (1.64 g, 4.6 mmol) in 50 mL EtOH was added K₂CO₃ (1.82 g, 11.04mmol) and 1-(3,4-dimethoxyphenyl)guanidine (1.31 g, 5.06 mmol), and thereaction was heated to 80° C. for 12 h. The reaction was then cooled to22° C., diluted with H₂O, and treated with 1 M HCl to pH 3. Theresulting solid was filtered and washed with H₂O, followed by EtOH andEt₂O. The crude product was dried in vacuo to give I-26 (1.8 g, 81%):HRMS Calcd. for C₂₀H₁₇IN₄O₃: 489.0423, Found 489.0431.

Example 11 Method I for the Synthesis of Compounds of Formula vi (SeeScheme 1)

4-(9-Chloro-5-methyl-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoicacid (I-69)

8-Chloro-4-dimethylamino-methylene-3-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-i) (0.125 g, 0.45 mmol) was dissolved in ethanol (5 mL), then4-guanidinebenzoic acid hydrochloride (0.116 g, 0.54 mmol) and potassiumcarbonate (0.153 g, 1.08 mmol) were added. The mixture was heated to140° C. in a microwave reactor for 10 minutes, after which it was pouredinto water (10 mL). Using 1M aqueous HCl, the mixture was acidified topH 4. The solid was filtered and washed with water and diethyl ether,then dried under reduced pressure at 40° C. for 16 h to give I-69 (5%yield) after purification by C-18 RP LC-MS chromatography: HRMS Calcd.for C₂₀H₁₅ClN₄O₃: 395.0910, Found 395.0938.

4-(9-Chloro-6-oxo-6,7-dihydro-5H-benzopyrimido[4,5]azepin-2-ylamino)-benzoicacid methyl ester (I-4)

In a manner similar to that described for Method I,(N-methyl-pyrrolidinone and NaHCO₃ used in place of EtOH and K₂CO₃),8-chloro-4-dimethyl-aminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and methyl 4-guanidinobenzoate hydrochloride were converted to I-4(59%): HRMS Calcd. for C₂₀H₁₅ClCN₄O₃: 395.0910, Found 395.0917.

4-(9-Chloro-7-methyl-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoicacid (I-7)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-1-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-m) and 4-guanidinobenzoic acid were converted to I-7 (30%): HRMSCalcd. for C₂₀H₁₅ClN₄O₃: 395.0910, Found 395.0923.

4-(7-Benzyl-9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoicacid (I-6)

In a manner similar to that described for method I,1-benzyl-8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-n) and 4-guanidinobenzoic acid were converted to I-6 (26%): MSm/z=471 (M+H) HRMS Calcd. for C₂₆H₁₉ClN₄O₃: 471.1223, Found 471.1310.

4-(9-Chloro-5,7-dimethyl-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoicacid (I-68)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-1,3-dimethyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-o) and 4-guanidinobenzoic acid were converted to I-68 (6%) afterpurification by C-18 RP LC-MS chromatography: HRMS Calcd. forC₂₁H₁₇ClN₄O₃: 409.1067, Found 409.1052.

4-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[415-d]azepin-2-ylamino)-benzoicacid (I-3)

In a manner similar to method I (DMF and NaHCO₃ were used in place ofEtOH and K₂CO₃),8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and 4-guanidinobenzoic acid were converted to I-3 (68%): HRMSCalcd. for C₁₉H₁₃ClN₄O₃: 381.0754, Found 381.0721.

4-(9-Chloro-6-oxo-7-phenyl-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoicacid (I-10)

In a manner similar to method I (DMF and NaHCO₃ were used in place ofEtOH and K₂CO₃),8-chloro-4-dimethylaminomethylene-1-phenyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-1) and 4-guanidinobenzoic acid were converted to I-10 (61%): HRMSCalcd. for C25H₁₇ClN₄O₃: 457.1067, Found 457.1076.

9-Chloro-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-2)

In a manner similar to method I (DMF and NaHCO₃ were used in place ofEtOH and K₂CO₃),8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]-azepine-2,5-dione(v-j) and 1-(3,4-dimethoxyphenyl)guanidine were converted to I-2 (87%):HRMS Calcd. for C20H₁₇ClN₄O₃: 397.1067, Found 397.109.

2-(3,4-Dimethoxy-phenylamino)-5,7-dihydro-1,3,7,8-tetraaza-dibenzo[a,c]cyclohepten-6-one(I-1)

In a manner similar to method H (NaHCO₃ used in place of K₂CO₃)(Z)-6-dimethylaminomethylene-6,7-dihydro-9H-pyrido[2,3-b]azepine-5,8-dione(v-h) and 1-(3,4-dimethoxyphenyl)guanidine were converted to I-1 (85%):MS R_(t)=1.3 min. m/z 364 (M+H).

4-(10-Methoxy-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoicacid (I-8)

In a manner similar to that described for Method H,4-dimethylamino-methylene-7-methoxy-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-e) and 4-guanidinobenzoic acid were converted to I-8 (48%): HRMSCalcd. for C₂₀H₁₆N₄O₄: 377.1249, Found 377.1231.

4-(10-Fluoro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoicacid (I-5)

In a manner similar to that described for Method H,4-dimethylaminomethylene-7-fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-f) and 4-guanidinobenzoic acid were converted to I-5 (98%): HRMSCalcd. for C₁₉H₁₃FN₄O₃: 365.1049, Found 365.1069.

4-(9-Methyl-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoicacid (I-9)

In a manner similar to that described for Method H,4-dimethylamino-methylene-8-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-g) and 4-guanidinobenzoic acid were converted to I-9 (36%): HRMSCalcd. for C₂₀H₁₆N₄O₃: 361.1300, Found 361.1306.

2-Amino-10-bromo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-44)

In a manner similar to that described in method H,7-bromo-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-k) and guanidine were converted to I-44 (79%): HRMS Calcd. forC₁₂H₉BrN₄O: 305.0037, Found 305.0042.

2-Amino-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylicacid (I-84)

In a manner similar to Method M,2-amino-10-bromo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-44) wasconverted to I-84 (97%) after purification by C-18 RP LC-MSchromatography. MS (FA) R_(t)=0.99 min, m/z=271 (M+H).

2-Amino-10-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-51)

In a manner similar to that described in method H,7-iodo-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-a) and guanidine were converted to I-51 (79%): HRMS Calcd. forC₁₂H₁₁N₄O: 352.9899, Found 352.9900.

N-(10-Iodo-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-yl)-benzamide(I-83)

2-Amino-10-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-51) (69.7mg, 0.20 mmol) was dissolved in pyridine (800 μL) and benzoyl chloride(23 mL, 0.20 mmol). The mixture was stirred at 110° C. for 1 h, thencooled to 22° C. Et₂O was added and the product was filtered from thesolution to give I-83 (37%): MS (FA) R_(t)=1.49 min, m/z=457 (M+H).

Example 12 Method M for the Synthesis of Compounds of Formula xii (SeeScheme 3)

2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylicacid (I-53)

To a solution of2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-30) (0.60 g, 1.20 mmol) in dry DMF (8 mL) was added Ac₂O (0.23 mL,2.44 mmol), HCOOLi (0.19 g, 3.66 mmol), LiCl (0.155 g, 3.66 mmol), andPd(OAc)₂ (0.01 g, 0.06 mmol). Lastly, i-Pr₂NEt (0.42 mL, 2.44 mmol) wasadded and the mixture heated for 16 h at 80° C. in a sealed tube. Thereaction mixture was then diluted with CH₂Cl₂ (30 mL), and the organiclayer was washed with H₂O (3×30 mL), dried over MgSO₄, filtered andconcentrated in vacuo to give crude product as a yellow solid. The solidwas treated with EtOAc and sonicated to provide a white solid which wascollected by filtration to provide I-53 (0.33 g, 71%): HRMS Calcd. forC₂₁H₁₈N₄O₅: 407.1355, Found 407.1364.

2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylicacid (I-43)

In a manner similar to Method M,2-(3,4-dimethoxy-phenylamino)-10-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-26) was converted to I-43 (100%): HRMS Calcd. for C₂₁H₈N₄O₅:407.1355, Found 407.1357.

Example 13 Method N for the Synthesis of Compounds of Formula xiii andxxix (see Schemes 3 and 7)

(2-{[2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carbonyl]-amino}-ethyl)-carbamicacid tert-butyl ester (I-71-a)

To a solution of2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylicacid (I-53) (75 mg, 0.18 mmol) in DMF (5 mL) was addedN,N-diisopropylethylamine (0.10 mL, 0.55 mmol), TBTU (65 mg, 0.20 mmol),and tert-butyl 2-aminoethylcarbamate (35.5 mg, 0.22 mmol). The reactionstirred at 22° C. overnight. The reaction mixture was diluted with H₂O,and the precipitate that formed was filtered, washed with H₂O and driedto give I-71-a [MS m/z=549 (M+H)] which was carried on crude to thedeprotection.

Example 14 Method K for Boc-Deprotections

2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylicacid (2-amino-ethyl)-amide (I-71)

To a mixture of(2-{[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carbonyl]-amino}-ethyl)-carbamicacid tert-butyl ester (I-71-a) (0.18 mmol) in 1:1 mixture of CH₂Cl₂:MeOH(4 mL) was added 4M HCl in dioxane (2 mL). The mixture stirred overnightand was concentrated. The mixture was purified by C-18 RP LC-MSchromatography to give I-71 (17%): HRMS Calcd. for C₂₃H₂₄N₆O₄: 449.1937,Found 449.1935.

2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylicacid (3-pyrrolidin-1-yl-propyl)-amide (I-77)

In a manner similar to that described in Method N,2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylicacid (I-43) and 3-(pyrrolidin-1-yl)propan-1-amine were converted to I-77(6%) after purification by C-18 RP LC-MS chromatography. HRMS Calcd. forC₂₈H₃₂N₆O₄: 517.2563, Found 517.2552.

2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylicacid (3-amino-propyl)-amide (I-76)

In a manner similar to that described in Method N,2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylicacid (I-43) and 3-amino-propyl-carbamic acid tert-butyl ester wereconverted to(3-{[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carbonyl]-amino}-propyl)-carbamicacid tert-butyl ester, which was subsequently deprotected (Method K) andpurified by C-18 RP LC-MS chromatography to give I-76 (14%): HRMS Calcd.for C₂₄H₂₆N₆O₄: 463.2093, Found 463.2085.

2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylicacid (2-pyrrolidin-1-yl-ethyl)-amide (I-75)

In a manner similar to that described for Method N,2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylicacid (I-43) and 2-(pyrrolidin-1-yl)ethanamine were converted to I-75(6%) after purification by C-18 RP LC-MS chromatography. HRMS Calcd. forC₂₇H₁₁N₆O₄: 503.2406, Found 503.2399.

10-(4-Amino-piperidine-1-carbonyl)-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-74)

In a manner similar to that described for Method N,2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylicacid (I-43) and piperidin-4-yl-carbamic acid tert-butyl ester wereconverted to{1-[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carbonyl]-piperidin-4-yl}-carbamicacid tert-butyl ester, which was subsequently deprotected according toMethod K. Purification by C-18 RP LC-MS chromatography afforded I-74(19%): HRMS Calcd. for C₂₆H₂₈N₆O₄: 489.2250, Found 489.2253.

2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylicacid (2-pyridin-4-yl-ethyl)-amide (I-48)

In a manner similar to that described for Method N,2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-10-carboxylicacid (I-43) and 2-(pyridin-4-yl)ethanamine were converted I-48 (6%):HRMS Calcd. for C₂₈H₂₆N₆O₄: 551.2093, Found 511.2098.

4-(10-Bromo-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoicacid (I-25)

In a manner similar to method I,7-bromo-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-k) and 4-guanidinobenzoic acid were converted to I-25 (22%): HRMSCalcd. for C₁₉H₁₃BrN₄O₃: 425.0249, Found 425.0269.

10-Bromo-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-18)

In a manner similar to method I (NaHCO₃ used instead of K₂CO₃),7-bromo-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-k) and 1-(3,4-dimethoxyphenyl)-guanidine were converted to I-18(74%): HRMS Calcd. for C₂₀H₁₇BrN₄O₃: 441.0562, Found 441.0548.

10-Bromo-2-(methyl-phenyl-amino)-5H7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-85)

A mixture of10-bromo-2-methanesulfinyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(100 mg) was stirred with N-methyl aniline (1 mL) and refluxed overnightat 150° C. Water was added and the product was extracted with methylenechloride, dried over MgSO₄, filtered and concentrated. Purification byC-18 RP LC-MS chromatography afforded I-85 (10%): MS m/z=395 (M+H).

9-Chloro-2-(3-hydroxymethyl-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]-azepine-6-one(I-79)

In a manner similar to method I,8-chloro-4-((dimethylamino)methylene)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and 1-(3-(hydroxymethyl)phenyl)-guanidine were converted to I-79(51%): HRMS Calcd. for C₁₉H₁₅ClN₄O₂: 367.0961, Found 367.0973.

9-Chloro-2-(4-chloro-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-11)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and 1-(4-chlorophenyl)guanidine were converted to I-11 (23%): HRMSCalcd. for C₁₈H₁₂Cl₂N₄O: 371.0466, Found 371.0471.

9-Chloro-2-(3-chloro-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-13)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and 1-(2-chlorophenyl)guanidine were converted to I-13 (26%): HRMSCalcd. for C₁₈H₁₂Cl₂N₄O: 371.0466, Found 371.0489.

9-Chloro-2-(2-chloro-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-12)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and 1-(2-chlorophenyl)guanidine were converted to I-12 (26%): HRMSCalcd. for C, H₁₂Cl₂N₄O: 371.0466, Found 371.0467.

9-Chloro-2-(4-methoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-14)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and 1-(4-methoxyphenyl)guanidine were converted to I-14 (39%):HRMS Calcd. for C₁₉H₁₁ClN₄O₂: 367.0960, Found 367.0975.

9-Chloro-2-(3-methoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-15)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and 1-(3-methoxyphenyl)guanidine were converted to I-15 (25%):HRMS Calcd. for C₁₁H₁₅ClN₄O₂: 367.0961, Found 367.0961.

9-Chloro-2-(2-methoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-16)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and 1-(2-methoxyphenyl)guanidine were converted to I-16 (39%):HRMS Calcd. for C₁₁H₁₁ClN₄O₂: 367.0961, Found 367.0947.

N′-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-yl)-N,N-dimethyl-guanidine(I-21)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and 1,1-dimethylbiguanidine hydrochloride were converted to I-21(9%): HRMS Calcd. for C₁₅H₁₅ClN₆O: 331.1074, Found 331.1063.

9-Chloro-2-methylamino-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-20)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and N-methylguanidine hydrochloride were converted to I-20 (32%):HRMS Calcd. for C₁₃H₁₁ClN₄O: 275.0699, Found 275.0708.

4-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-butyricacid (I-19)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and 4-guanidino butyric acid were converted to I-19 (6%): HRMSCalcd. for C₁₆H₁₁ClN₄O₃: 347.091, Found 347.092.

9-Chloro-2-dimethylamino-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-22)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and 1,1-dimethylguanidine sulfate were converted to I-22 (42%):HRMS Calcd. for C₁₄H₁₃ClN₄O: 289.0856, Found 289.0843.

10-Chloro-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-24)

In a manner similar to that described for method I,7-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-d) and N-(3,4-dimethoxyphenyl)guanidine nitrate were converted toI-24 (67%): HRMS Calcd. for C₂₀H₁₇ClN₄O₃: 397.1067, Found 397.1059.

2-(3,4-Dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-27)

In a manner similar to that described for method I,4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-c)and N-(3,4-dimethoxyphenyl)guanidine nitrate were converted to I-27(58%): HRMS Calcd. for C₂₀H₁₈N₄O₃: 363.1457, Found 363.1441.

9-Chloro-2-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-28)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and N-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-guanidine nitrate wereconverted to I-28 (71%): HRMS Calcd. for C₂₀H₁₅ClN₄O₃: 395.091, Found395.0912.

9-Chloro-2-(3,4-dimethyl-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-29)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and N-(3,4-dimethyl-phenyl)-guanidine nitrate were converted toI-29 (59%): HRMS Calcd. for C₂₀H₁₇ClN₄O: 365.1169, Found 365.1143.

2-(Benzo[1,3]dioxol-5-ylamino)-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-34)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and N-benzo[1,3]dioxol-5-yl-guanidine nitrate were converted toI-34 (32%): HRMS Calcd. for C₁₉H₁₃ClN₄O₃: 381.0754, Found 381.0759.

9-Chloro-2-(3,5-dimethyl-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-35)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and N-(3,5-dimethyl-phenyl)-guanidine nitrate were converted toI-35 (71%): HRMS Calcd. for C₂₀H₁₇ClNO₄: 365.1169, Found 365.1190.

9-Chloro-2-(4-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-36)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and N-(4-iodo-phenyl)-guanidine nitrate were converted to I-36(62%): HRMS Calcd. for C₁₈H₁₂ClIN₄O: 462.9822, Found 462.9818.

Example 15 Method O for the Synthesis of Compounds of Formula xiv andxxi (see Schemes 3 and 5)

2-(3,4-Dimethoxy-phenylamino)-9-trimethylsilanylethynyl-5H,7H-benzo[b]-pyrimido[4,5-d]azepin-6-one(I-33-a)

To a solution of2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-30) (300 mg, 0.614 mmol) in 4 mL DMF at 22° C. was addeddichlorobis(triphenylphosphine)palladium (15 mg, 0.02 mmol), copperiodide (9 mg, 0.05 mmol), and triethylamine (0.34 mL, 2.45 mmol). Thesolution was degassed with argon, and stirred at 22° C. for 1 h.(Trimethylsilyl)acetylene (120 mg, 1.22 mmol) was added and the solutionwas stirred at 22° C. for 2 h. Water was added to the reaction mixture,and the resulting precipitate was filtered and purified by silica gelchromatography (ISCO, elution with 30-100% ethyl acetate in hexanes) togive I-33-a (180 mg, 64%): MS m/z=459 (M+H).

Example 16 Method for Ethynyl Trimethylsilane Deprotection

2-(3,4-Dimethoxy-phenylamino)-9-ethynyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-33)

To a solution of2-(3,4-dimethoxy-phenylamino)-9-trimethylsilanyl-ethynyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-33-a) (180 mg, 0.39 mmol) in methanol (4 mL) was added potassiumcarbonate (217 mg, 1.57 mmol). The reaction stirred at 22° C. overnight.The mixture was then concentrated in vacuo, redissolved in water (100mL) and extracted with methylene chloride (3×100 mL). The organicfractions were combined, washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give I-33 (50 mg, 99%): HRMS Calcd. forC₂₂H₁₈N₄O₃: 387.1457, Found 387.1451.

9-Chloro-2-(4-ethynyl-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-45)

In a manner similar to that described for Method O,9-chloro-2-(4-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-36) and ethynyltrimethylsilane were converted to9-chloro-2-(4-trimethylsilanylethynyl-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one,which was deprotected in a manner similar to I-33 to give I-45 (38%):HRMS Calcd. for C₂₀H₁₃ClN₄O: 361.0856, Found 361.0848.

2-[4-(3-Amino-prop-1-ynyl)-phenylamino]-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(HCl salt) (I-46)

In a manner similar to that described for Method O,9-chloro-2-(4-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-36) and tert-butyl prop-2-ynylcarbamate were converted to{3-[4-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-phenyl]-prop-2-ynyl}-carbamicacid tert-butyl ester, which was deprotected according to Method K togive I-46 (29%): HRMS Calcd. for C₂₁H₁₆ClN₅O: 390.1121, Found 390.1120.

9-Chloro-2-[4-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenylamino]-5H,7H-benzo[b]-pyrimido[4,5-d]azepin-6-one(I-47)

In a manner similar to that described for Method O,9-chloro-2-(4-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-36) and 1-(prop-2-ynyl)pyrrolidine were converted to I-47 (52%): HRMSCalcd. for C₂₅H₂₂ClN₅O: 444.1591, Found 444.1589.

9-Chloro-2-[4-(3-hydroxy-prop-1-ynyl)-phenylamino]-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-54)

In a manner similar to that described for Method O,9-chloro-2-(4-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-36) and prop-2-yn-1-ol were converted to I-54 (86%): HRMS Calcd. forC₂₁H₁₁ClN₄O₂: 391.0961, Found 391.0960.

9-Chloro-2-(3,5-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-55)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and N-(3,5-dimethoxy-phenyl)-guanidine nitrate were converted toI-55 (62%): HRMS Calcd. for C₂₀H₁₇ClN₄O₃: 397.1067, Found 397.1056.

Example 17 Method P for the Synthesis of Compounds of Formula xv andxxii (See Schemes 3 and 5)

9-Chloro-2-[4-(3-pyrrolidin-1-yl-propyl)-phenylamino]-5H,7H-benzo[b]pyrimido[4,5-d]-azepin-6-one(I-66)

To a solution of9-chloro-2-[4-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenylamino]-5H,7Hbenzo[b]pyrimido[4,5-d]azepin-6-one (I-47) (0.082 g, 0.19 mmol) in EtOH(5 mL) was added Pd/C (10% wt, ˜50% H₂O, 0.01 g) and the mixture wasplaced under H₂ (1 atm) and stirred for 12 h at 22° C. The reactionmixture was filtered through Celite® and the filtrate concentrated invacuo to give crude product as a yellow oil. Purification by C-18 RPLC-MS chromatography afforded I-66 (0.046 g, 56%): HRMS Calcd. forC₂₅H₂₆ClN₅O: 448.1904, Found 448.1907.

2-[4-(3-Amino-propyl)-phenylamino]-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-57)

In a manner similar to that described for Method P,2-[4-(3-amino-prop-1-ynyl)-phenylamino]-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-46) was converted to I-57 (24%): HRMS Calcd. for C₂₁H₂₀ClN₅O:394.1434, Found 394.1448.

9-Chloro-2-(3-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-58)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and N-(3-iodo-phenyl)-guanidine nitrate were converted to I-58(50%): HRMS Calcd. for C₁₈H₁₂ClIN₄O: 462.9822, Found 462.9838.

9-Chloro-2-(3-hydroxy-4-methoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-65)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and N-(3-hydroxy-4-methoxy-phenyl)-guanidine nitrate wereconverted to I-65 (69%): HRMS Calcd. for C₁₉H₁₁ClN₄O₃: 383.091, Found383.0913.

2-[3-(3-Amino-prop-1-ynyl)-phenylamino]-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-67)

In a manner similar to that described for Method O,9-chloro-2-(3-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-58) and tert-butyl prop-2-ynylcarbamate was converted to{3-[3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-phenyl]-prop-2-ynyl}-carbamicacid tert-butyl ester, which was subsequently deprotected according toMethod Kto give I-67 (62%): HRMS Calcd. for C₂₁H₁₆ClN₅O: 390.1121, Found390.1117.

[3-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-phenyl]-acetonitrile(I-78)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and N-(3-cyanomethyl-phenyl)-guanidine nitrate were converted toI-78 (6%): HRMS Calcd. for C₂₀H₁₄ClN₅O: 376.0965, Found 376.0994.

9-Chloro-2-[3-(2-hydroxy-ethyl)-phenylamino]-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-80)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and N-[3-(2-hydroxy-ethyl)-phenyl]-guanidine nitrate wereconverted to I-80 (65%): HRMS Calcd. for C₂₀H₁₇ClN₄O₂: 381.1118, Found381.1126.

9-Chloro-2-[3-(3-pyrrolidin-1-yl-prop-1-ynyl)-phenylamino]-5H,7H-benzo[b]-pyrimido[4,5-d]azepin-6-one(I-89)

In a manner similar to that described for Method O,9-chloro-2-(3-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(v-j) and 1-(prop-2-ynyl)pyrrolidine were converted to I-89 (46%): MS(AA) R_(t)=1.32 min, m/z=444 (M+H).

3-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzonitrile(I-90)

In a manner similar to that described for method I,8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and N-(3-cyano-phenyl)-guanidine nitrate were converted to I-90(58%): MS (AA) R_(t)=1.79 min, m/z=362 (M+H).

Example 18 Method R for the Reduction of Nitriles

2-[3-(2-Amino-ethyl)-phenylamino]-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-86)

To a solution of[3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-phenyl]-acetonitrile(I-78) (0.131 g, 0.349 mmol) in saturated NH₃ in MeOH solution (50 mL)was added a catalytic amount of Raney 2800 Ni in H₂O and the mixture wasplaced under H₂ (50 psi) and stirred for 12 h at 22° C. The reactionmixture was filtered through Celite® and the filtrate concentrated invacuo to give crude product as a yellow oil. Purification by C-18 RPLC-MS chromatography afforded I-86 (0.019 g, 14%): MS (AA) R_(t)=1.25min, m/z=380 (M+H).

2-(3,4-Dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-30)

In a manner similar to that described for method H,4-dimethylaminomethylene-8-iodo-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-b) was converted to I-30 (84%): HRMS Calcd. for C₂₀H₁₇IN₄O₃:489.0423, Found 489.0443.

2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylicacid amide (I-70)

In a manner similar to that described for Method N,2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylicacid (I-53) and NH₃ gas were converted to2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylicacid amide. The mixture was purified by C-18 RP LC-MS chromatography toafford pure I-70 (6%): HRMS Calcd. for C₂₁H₁₉N₅O₅₄: 406.1515, Found406.1519.

2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylicacid (3-amino-propyl)-amide (I-72)

In a manner similar to that described for Method N,2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylicacid (I-53) and tert-butyl 4-aminopropylcarbamate were converted to(2-{[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carbonyl]-amino}-ethyl)-carbamicacid tert-butyl ester, which was subsequently deprotected (Method K) togive I-72 (30%): HRMS Calcd. for C₁₄H₂₆N₆O₄: 463.2093, Found 463.2078.

2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylicacid (4-amino-butyl)-amide (I-73)

In a manner similar to that described Method N,2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylicacid (I-53) and tert-butyl 4-aminobutylcarbamate were converted to(2-{[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carbonyl]-amino}-ethyl)-carbamicacid tert-butyl ester, which was subsequently deprotected (Method K) togive I-73 (25%): HRMS Calcd. for C₂₅H₂₈N₆O₄: 477.2250, Found 477.2250.

3-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoicacid (I-62-a)

In a manner similar to method I,8-chloro-4-((dimethylamino)methylene)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and 3-guanidino-benzoic acid were converted to I-62-a (72%): MSm/z=381 (M+H).

N-(2-Amino-ethyl)-3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzamide(I-62)

In a manner similar to Method N,3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoicacid (I-62-a) and tert-butyl 4-aminoethylcarbamate were converted to13-[3-(9-chloro-6-oxo-6,7-dihydro-H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoylamino]-ethyl)-carbamicacid tert-butyl ester. Subsequent deprotection (Method K) andpurification by C-18 RP LC-MS chromatography afforded I-62 (13%): HRMSCalcd. for C₂₁H₁₉ClN₆O₂: 423.1336, Found 423.1346.

N-(3-Amino-propyl)-3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzamide(I-63)

In a manner similar to Method N,3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoicacid (I-62-a) and tert-butyl 4-aminopropylcarbamate were converted to{3-[3-(9-chloro-6-oxo-6,7-dihydro-H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoylamino]-propyl}-carbamicacid tert-butyl ester. Subsequent deprotection (Method K) andpurification by C-18 RP LC-MS chromatography afforded I-63 (16%): HRMSCalcd. for C₂H₂₁ClN₆O₂: 437.1492, Found 437.1480.

N-(4-Amino-butyl)-3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzamide(I-64)

In a manner similar to Method N,3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoicacid (I-62-a) and tert-butyl 4-aminobutylcarbamate were converted to{4-[3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoylamino]-butyl}-carbamicacid tert-butyl ester. Subsequent deprotection (Method K) andpurification by C-18 RP LC-MS chromatography afforded I-64 (10%): HRMSCalcd. for C₁₁H₂₃ClN₆O₂: 451.1649, Found 451.1668.

9-Chloro-2-(3,4-dimethoxybenzyl)-5H,7H-benzo[b]pyrimido[45-d]azepin-6-one(I-17)

In a manner similar to method I,8-chloro-4-((dimethylamino)methylene)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) and 1-(3,4-dimethoxybenzyl)guanidine were converted to I-17 (41%):HRMS Calcd. for C₂₁H₁₉ClN₄O₃: 411.1223, Found 411.1241.

2-(3,4-Dimethoxy-phenylamino)-9-ethyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-37)

In a manner similar to that described for Method P,2-(3,4-dimethoxy-phenylamino)-9-ethynyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-33) was converted to I-37 (23%): HRMS Calcd. for C₂₂H₂₂N₄O₃:391.1770, Found 391.1796.

2-(3,4-Dimethoxy-phenylamino)-9-(3-pyrrolidin-1-yl-prop-1-ynyl)-5H,7Hbenzo[b]pyrimido[4,5-d]azepin-6-one (I-32)

In a manner similar to that described above for Method O,2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-30) and 1-(prop-2-ynyl)pyrrolidine were converted to I-32 (42%): HRMSCalcd. for C₂₇H₂₇N₅O₃: 470.2192, Found 470.2192.

2-(3,4-Dimethoxy-phenylamino)-9-(3-pyrrolidin-1-yl-propyl)-5H,7H-benzo[b]-pyrimido[4,5-d]azepin-6-one(HCl) (I-49)

In a manner similar to that described above for Method P,2-(3,4-dimethoxy-phenylamino)-9-(3-pyrrolidin-1-yl-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-32) was converted to2-(3,4-dimethoxy-phenylamino)-9-(3-pyrrolidin-1-yl-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one,which was then converted to the HCl salt as described in Method K togive I-49 (9%): HRMS Calcd. for C₂₇H₃₁N₅O₃: 474.2505, Found 474.2491.

{3-[2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-9-yl]-prop-2-ynyl}-carbamicacid tert-butyl ester (I-39)

In a manner similar to that described for Method O,2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-30) and tert-butyl prop-2-ynylcarbamate were converted to I-39 (31%):HRMS Calcd. for C₂₉H₂₉N₅O₅: 516.2246, Found 516.2244.

9-(3-Amino-prop-1-ynyl)-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(HCl) (I-38)

In a manner similar to that described for Method K,{3-[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-9-yl]-prop-2-ynyl}-carbamicacid tert-butyl ester (I-39) was converted to the HCl salt of I-38(30%): HRMS Calcd. for C₂₃H₂₁N₅O₃ 416.1720, Found 416.1722.

9-(3-Amino-propyl)-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-50)

In a manner similar to that described for Method P,{3-[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-9-yl]-prop-2-ynyl}-carbamicacid tert-butyl ester (I-39) was converted to{3-[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-9-yl]-propyl}-carbamicacid tert-butyl ester (I-41: HRMS Calcd. for C₂₈H₃₃N₅O₅: 520.2559, found520.2551), which was subsequently deprotected (Method K) to give I-50(80%) HRMS Calcd. for C₂₃H₂₅N₅O₃: 420.2035, Found 420.2045.

2-(3,4-Dimethoxy-phenylamino)-9-(3-hydroxy-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-52)

In a manner similar to that described for Method O,2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-30) and prop-2-yn-1-ol were converted to I-52 (38%): HRMS Calcd. forC₂₃H₂₀N₄O₄: 417.1562, Found 417.1551.

2-(3,4-Dimethoxy-phenylamino)-9-(3-hydroxy-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-81) and2-(3,4-Dimethoxy-phenylamino)-9-propyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-82)

In a manner similar to that described for Method P (50 psi H₂),2-(3,4-dimethoxy-phenylamino)-9-(3-hydroxy-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-52) was converted to I-81 (8% yield): HRMS Calcd. for C₂₃H₂₄N₄O₄:421.1875, Found 421.1881 and I-82 (8% yield) HRMS Calcd. for C₂₃H₂₄N₄O₃:405.1926, Found 405.1930. The two compounds were separated by columnchromatography in 0%-10% MeOH/CH₂Cl₂.

2-(3,4-Dimethoxy-phenylamino)-9-(3-dimethylamino-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-91)

In a manner similar to that described for Method O,2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-30) and N,N-dimethylprop-2-yn-1-amine were converted to2-(3,4-dimethoxy-phenylamino)-9-(3-dimethylamino-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one,which was purified by C-18 RP LC-MS chromatography to afford pure I-91(16%): MS (FA) R_(t)=0.98 min, m/z=444 (M+H).

2-(3,4-Dimethoxy-phenylamino)-9-(3-dimethylamino-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-88)

In a manner similar to that described for Method P,2-(3,4-dimethoxy-phenylamino)-9-(3-dimethylamino-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-91) was converted to I-88 (72%): MS R_(t)=1.01 min, m/z=448 (M+H).

2-(3,4-Dimethoxy-phenylamino)-9-(3-methylamino-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(HCl) (I-87)

In a manner similar to that described for Method O,2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-30) and N-methylprop-2-yn-1-amine were converted to2-(3,4-dimethoxy-phenylamino)-9-(3-methylamino-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one.The crude product (unstable) was carried on in a similar manner to thatdescribed for Method P to give I-87, which was converted to the HCl salt(40%): MS R_(t)=0.98 min, m/z=434 (M+H).

Example 19 Method Q for the Preparation of Compounds of Formula xvi

2-(3,4-Dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carbonitrile(I-92)

To a solution of2-(3,4-dimethoxy-phenylamino)-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-30) (100 mg, 0.210 mmol) in 4 mL anhydrous DMF at room temperaturewas added zinc cyanide (14 mg, 0.120 mmol),tris(dibenzylideneacetone)dipalladium (9.5 mg, 0.01 mmol),1,1′-bis(diphenyl-phosphino)ferrocene (14.0 mg, 0.02 mmol) and a drop ofH₂O. The solution was degassed with argon then stirred at 1° C. for 16h. The solution was allowed to cool to 22° C., then diluted with EtOAcand saturated aqueous sodium bicarbonate. The organic layer was thenwashed with H₂O and brine, dried over Na₂SO₄, and concentrated in vacuo.The product was recrystallized in methanol and CH₂Cl₂ to give I-92(92%): MS R_(t)=2.49 min, m/z=388 (M+H).

2-(3,4-Dimethoxy-phenylamino)-10-(3-pyrrolidin-1-yl-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-31)

In a manner similar to Method O,2-(3,4-dimethoxy-phenylamino)-10-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-26) and 1-(prop-2-ynyl)pyrrolidine were converted to I-31 (29%): HRMSCalcd. for C₂₇H₃₁N₅O₃: 470.2192, Found 470.2185.

2-(3,4-Dimethoxy-phenylamino)-10-(3-pyrrolidin-1-yl-propyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-56)

In a manner similar to Method P,2-(3,4-dimethoxy-phenylamino)-10-(3-pyrrolidin-1-yl-prop-1-ynyl)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-31) was converted to I-56 (42%): HRMS Calcd. for C₂₇H₃₁N₅O₃:474.2505, Found 474.2498.

10-(3-Amino-prop-1-ynyl)-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]-pyrimido[4,5-d]azepin-6-one(HCl) (I-59)

In a manner similar to Method O,2-(3,4-dimethoxy-phenylamino)-10-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-26) and tert-butyl prop-2-ynylcarbamate were converted to{3-[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-10-yl]-prop-2-ynyl}-carbamicacid tert-butyl ester. Subsequent deprotection (Method K) andpurification by C-18 RP LC-MS chromatography afforded the HCl salt ofI-59 (24%): HRMS Calcd. for C₂₃H₂₁N₅O₃: 416.1722, Found 416.1725.

10-(3-Amino-propyl)-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-60)

In a manner similar to Method P,10-(3-amino-prop-1-ynyl)-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-59) was converted to I-60 (41%): HRMS Calcd. for C₂₃H₂₅N₅O₃:420.2035, Found 420.2043.

2-(3,4-Dimethoxy-phenylamino)-9-methyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-42)

In a manner similar to method I,4-((dimethylamino)methylene)-8-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-g) and 1-(3,4-dimethoxyphenyl)guanidine were converted to I-42 (57%):HRMS Calcd. for C₂₁H₂₀N₄O₃: 377.1613, Found 377.1613.

9-Chloro-2-phenylamino-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-61)

To a solution of2-amino-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-23) (148mg, 0.568 mmol), 1-bromobenzene (0.072 mL, 0.681 mmol), Cs₂CO₃ (333 mg,1.02 mmol), and BINAP (53 mg, 0.085 mmol) in 4 mL toluene was addedPd(OAc)₂ (12.8 mg, 0.057 mmol), and the reaction was stirred at 100° C.for 12 h. The reaction mixture was then treated with H₂O and extractedwith CH₂Cl₂ (2×30 mL). The organic fractions were combined, filtered,dried over MgSO₄ and concentrated in vacuo to give an orange oil whichwas purified by C-18 RP LC-MS chromatography to afford I-61 (0.9%): HRMSCalcd. for C₁₈H₁₃ClN₄O: 337.0856, Found 337.0853.

2-Amino-9-chloro-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-23)

In a manner similar to that described for method I (NaHCO₃ used insteadof K₂CO₃), guanidine hydrochloride and8-chloro-4-((dimethylamino)methylene)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(v-j) were converted to I-23 (72%): HRMS Calcd. for C₁₂H₉ClN₄O:261.0543, Found 261.0543.

8-Chloro-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(I-40-a)

To a stirring solution of8-chloro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (iv-j) (1.2 g, 5.7mmol) in DMF (75 mL) was added cesium carbonate (5.63 g, 17.3 mmol) and2-(3-bromopropyl)isoindoline-1,3-dione (1.7 g, 6.34 mmol). The solutionwas stirred at room temperature for 12 h and then sodium iodide (100 mg)was added. The reaction was stirred at room temperature for 72 h. Thesolution was then diluted with dichloromethane and washed with water.The organics were dried over magnesium sulfate and concentrated. Columnchromatography (1:1 ethyl acetate/hexanes) yielded I-40-a which wascarried on crude: MS m/z=397 (M+H).

8-Chloro-4-((dimethylamino)methylene)-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(I-40-b)

In a manner similar to that described for method G,8-chloro-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(I-40-a) and DMF-DMA were converted to I-40-b and carried on crude: MSm/z=452 (M+H).

2-{3-[9-Chloro-2-(3,4-dimethoxy-phenylamino)-6-oxo-5,6-dihydrobenzo[b]pyrimido[4,5-d]azepin-7-yl]-propyl}-isoindole-1,3-dione (I-40-c)

In a manner similar to that described for method I (NaHCO₃ used insteadof K₂CO₃), 1-(3,4-dimethoxyphenyl)guanidine and8-chloro-4-((dimethylamino)-methylene)-1-(3-(1,3-dioxoisoindolin-2-yl)propyl)-3,4-dihydro-1H-benzo[b]azepine-2,5-dione(I-40-b) were converted to I-40-c and carried on crude: MS m/z=584(M+H).

7-(3-Amino-propyl)-9-chloro-2-(3,4-dimethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-40)

To a stirring solution of2-{3-[9-chloro-2-(3,4-dimethoxy-phenylamino)-6-oxo-5,6-dihydrobenzo[b]pyrimido[4,5-d]azepin-7-yl]-propyl}-isoindole-1,3-dione(I-40-c) (51 mg, 0.09 mmol) in ethanol (1.5 mL) was added methylamine(40% by wt in H₂O, 0.5 mL). After stirring for 2.5 h at roomtemperature, the solution was diluted with dichloromethane and washedwith water. The organics were dried over magnesium sulfate andconcentrated. Preparative HPLC gave I-40: MS R_(t)=1.32 min. m/z=454(M+H).

9-Chloro-2-methanesulfonyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-14-a)

Sodium ethoxide (340 mL, 1.05 mmol) and S-methyl-isothiourea-hemisulfate(146 mg, 1.05 mmol) was suspended in absolute EtOH (3 mL). Thesuspension was stirred for 1 h, then the Na₂SO₄ was removed byfiltration. The filtrate was then added to enamine v-j (253 mg, 0.956mmol) in absolute EtOH (1 mL). The reaction mixture was microwaved at160° C. for 20 min. EtOH was removed and the remaining solid was treatedwith water. The resulting precipitate was filtered, washed with waterand ether, and dried to give 243 mg of the crude sulfide (87% crude).

To a suspension of crude sulfide (96 mg, 0.33 mmol) in anhydrous CH₂Cl₂(6.5 mL) was added MCPBA (342 mg, 1.98 mmol). After the reaction wasstirred at 22° C. for 12 h, the reaction mixture was washed with 1N NaOH(0.35 mL) and water (15 mL). The aqueous layer was extracted with CH₂Cl₂and then EtOAc. The combined organic layers were dried (MgSO₄),concentrated and chromatographed to give 63 mg of pale yellow solidI-14-a (51% over two steps). MS 324/326 (M+H).

Example 20 Method J for the Preparation of Compounds of Formula vi

9-Chloro-2-(4-trifluoromethoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one

In a glovebox, to a vial containing 4-(trifluoromethoxy)aniline (531 mg,3 mmol) in THF (0.8 mL) and toluene (2.4 mL), was slowly added 2Msolution of AlMe₃ in toluene (1.5 mL, 3 mmol). The solution was stirredat 50° C. for 2 h. The resulting solution was then added to a vialcontaining sulfone viii (97 mg, 0.3 mmol). The reaction mixture wasstirred at 60° C. overnight, and then concentrated. A fine suspension ofKF (192 mg, 3.3 mmol) in DCM (1.6 mL) was added to the dried residue inthe vial, followed by H₂O (0.05 mL). The suspension was sonicated for 20min, and then a spatula-full of Celite® was added to the vial, followedby another 20 min of sonication. The suspension was filtered and washedwith EtOAc and MeOH, and the filtrate was evaporated. To the resultingresidue was added DCM (10 mL) and DMF (5 mL), PL-CHO resin (PolymerLaboratories, Inc., Amherst, Mass.) (2.4 g, 7.2 mmol), and 1M AcOH inDCM (0.72 mL, 0.72 mmol). The resin mixture was shaken at rt overnight.The resin was filtered off and the filtrate was concentrated. Theresulting mixture was purified by C-18 RP LC-MS chromatography toprovide9-Chloro-2-(4-trifluoro-methoxyphenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(25.5%): ¹H NMR (300 MHz, acetone-d6): δ 8.53 (s, 1H), 8.18 (d, J=9.0Hz, 1H), 8.05 (d, J=9.0 Hz, 1H), 8.03-8.06 (m, 1H), 7.38-7.41 (m, 2H),7.28-7.31 (m, 2H), 3.49 (s, 2H), 2.84 (br. s, 1H); MS m/z=421 (M+H).

Example 21 Method J for the Preparation of Compounds of Formulavi—Library Synthesis

To each vial containing sulfone viii (48 mg, 0.15 mmol), was added 0.2Msolution of an amine in THF/toluene (1:1) (0.3-0.6 mmol). For insolubleamines, DMF (0.2 mL to 1.6 mL) was added; and for amine salts, Hunig'sbase was added to neutralize the amine. Hunig's base (0.15 mL) was addedto the solution. The solutions were shaken at 70° C. overnight. Thereaction mixtures were concentrated, and the residues were dissolved inDCM (1.0 mL) and DMF (1.0 mL). PL-CHO resins (Polymer Laboratories,Inc., Amherst, Mass.) (400 mg, 1.2 mmol), and 1M AcOH in DCM (0.12 mL,0.12 mmol) were added to the solution. The resin mixtures were shaken atrt overnight. The resins were filtered off and the filtrates wereconcentrated. Each resulting residue was purified by reverse phase HPLCusing an Agilent HPLC equipped with a SunFire™ column (WatersCorporation), Method Formic Acid.

9-Chloro-2-{[2-(1H-imidazol-5-yl)ethyl]amino}-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one(I-236)

To a vial containing sulfone viii (48 mg, 0.15 mmol), was added 0.2Msolution of 2-(4-imidazolyl)ethylamine in THF/toluene (1:1) (0.15-0.30mL, 0.3-0.6 mmol). Hunig's base (0.15 mL) was added to the solution. Thesolution was shaken at 70° C. overnight. The reaction mixture wasconcentrated, and the residue was dissolved in DCM (1.0 mL) and DMF (1.0mL). PL-CHO resins (400 mg, 1.2 mmol), and 1M AcOH in DCM (0.12 mL, 0.12mmol) were added to the solution. The resin mixture was shaken at roomtemperature overnight. The resins were filtered off and the filtrate wasconcentrated. The resulting residue was purified by RP-HPLC using anAgilent HPLC equipped with a SunFire™ column (Waters Corporation),Method Formic Acid, to give compound I-236 (47.0%): ¹H NMR (300 MHz,CD₃OD): δ 8.29-7.98 (m, 4H), 7.28-7.06 (m, 4H), 3.68 (br. t., 2H), 3.28(s, 2H), 2.93 (br. t, 2H); MS m/z=355 (M+H).

Example 22 Method S for Guanidine Synthesis

1-(3,4-Dimethoxyphenyl)guanidine (HNO₃ salt) (xix-a)

To a vigorously stirred solution of 3,4-dimethoxyaniline (15.3 g, 0.1mol) in EtOH (60 mL) at 0° C. was added nitric acid (69%, 9.0 mL, 0.1mol) dropwise. A solution of cyanamide (4.6 g, 0.1 mol) in HO (8.5 mL)was added and the solution was heated at reflux for 3 h. The mixture wasthen diluted with EtOH (50 mL), cooled to 4° C. The resulting goldenneedles were collected and dried in vacuo to provide xix-a as the nitricacid salt (14.7 g, 57%): MS m/z=196 (M+H).

3-Guanidino-benzoic acid (HNO₃ salt) (xix-b)

In a manner similar to that described for method S, 3-amino-benzoic acidwas converted to xix-b (78%): MS m/z=178 (M−H).

N-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-guanidine (HNO₃ salt) (xix-c)

In a manner similar to that described in method S,2,3-dihydro-benzo[1,4]dioxin-6-ylamine was converted to xix-c (23%): MSm/z=194 (M−H).

N-(3,4-Dimethyl-phenyl)-guanidine (HNO₃ salt) (xix-d)

In a manner similar to that described in method S,3,4-dimethyl-phenylamine was converted to xix-d (31%): MS m/z=164 (M−H).

N-(3,5-Dimethyl-phenyl)-guanidine (HNO₃ salt) (xix-e)

In a manner similar to that described in method S,3,5-dimethyl-phenylamine was converted to xix-e (20%): MS m/z=164 (M−H).

N-(3,5-Dimethoxy-phenyl)-guanidine (HNO₃ salt) (xix-f)

In a manner similar to that described in method S,3,5-dimethoxy-phenylamine was converted to xix-f (39%): MS m/z=196(M−H).

N-(4-Iodo-phenyl)-guanidine (HNO₃ salt) (xix-g)

In a manner similar to that described in method S, 4-iodo-phenylaminewas converted to xix-g (99%): MS m/z=262 (M−H).

N-(3-Iodo-phenyl)-guanidine (HNO₃ salt) (xix-h)

In a manner similar to that described in method S, 3-iodo-phenylaminewas converted to xix-h (42%): MS m/z=262 (M−H).

N-(3-Hydroxy-4-methoxy-phenyl)-guanidine (HNO₃ salt) (xix-i)

In a manner similar to that described in method S,5-amino-2-methoxy-phenol was converted to xix-i (27%): MS m/z=182 (M−H).

N-Benzo[1,3]dioxol-5-yl-guanidine (HNO₃ salt) (xix-j)

In a manner similar to that described in method S,benzo[1,3]dioxol-5-ylamine was converted to xix-j (59%): MS m/z=180(M−H).

1-(3-(Hydroxymethyl)phenyl)guanidine (HNO₃ salt) (xix-k)

In a manner similar to that described for method S,(3-aminophenyl)-methanol was converted to xix-k: MS m/z=166 (M−H).

Example 23 Method V for Nitro-Group Reduction

(3-Amino-phenyl)-acetonitrile (xix-l-1)

To a solution of 3-nitro-phenyl-acetonitrile (3.20 g, 19.7 mmol) in MeOH(50 mL) was added Pd/C (10% wt, ˜50% H₂O, 0.32 g) and the mixture wasplaced under H2 (80 psi) and stirred for 2 days at 22° C. The reactionmixture was filtered through Celite® and the filtrate concentrated invacuo to give crude product as a yellow oil. The residue was purified bysilica gel chromatography (ISCO, elution with 0-10% ethyl acetate inhexanes) to give xix-l-1 (1.15 g, 44%): MS m/z=133 (M−H).

N-(3-Cyanomethyl-phenyl)-guanidine (HNO₃ salt) (xix-l)

In a manner similar to that described in method S,3-amino-phenyl-acetonitrile was converted to xix-1 (81%): MS m/z=175(M−H).

2-(3-Amino-phenyl)-ethanol (xix-m-1)

In a manner similar to that described for method V,2-(3-nitrophenyl)-ethanol was converted to xix-m-1 (89%): MS m/z=138(M−H).

N-[3-(2-Hydroxy-ethyl)-phenyl]-guanidine (HNO₃ salt) (xix-m)

In a manner similar to that described in method S,2-(3-amino-phenyl)-ethanol was converted to xix-m: MS m/z=180 (M−H).

N-(3-Cyano-phenyl)-guanidine (HNO₃ salt) (xix-n)

In a manner similar to that described in method S, 3-amino-benzonitrilewas converted to xix-n (42%): MS m/z=161 (M−H).

Example 24 Method T for Guanidine Synthesis

1-(3,4-Dimethoxybenzyl)guanidine (H₂SO₃ salt) (xix-o)

Formamidinesulfinic acid (2.65 g, 24.5 mmol) was dissolved in aceticacid (8.3 mL) and cooled to 10° C. Peracetic acid (5.7 mL, 27 mmol) wasslowly added to the cooled solution. After addition was complete, thereaction was warmed slowly to 22° C. and stirred for 3 h. The solid wasfiltered and washed with ethanol (200 proof) then dried in vacuo to givean unstable intermediate 2.44 g (80%). The intermediate was dissolved inmixture of CH₃CN (5 mL) and MeOH (10 mL). Then(3,4-dimethoxy-phenyl)methanamine (1.27 mL, 8.39 mmol) was added slowlyand stirred at 22° C. The reaction was stirred for 12 h and thenconcentrated in vacuo to give xix-o (2.44 g, 99%).

4-Guanidino-benzoic acid methyl ester (HCl salt) (xix-p)

4-guanidine-benzoic acid (1.12 g) was dissolved in anhydrous methanol(25 mL) and HCl in diethyl ether was added (1M; 800 μL). The mixture washeated in a sealed tube for 16 hours. Solvents were removed underreduced pressure to provide xix-p as a white solid (1.17 g, 99%).

Example 25 Method U for Guanidine Synthesis

N-(3,4-dimethylisoxazol-5-yl)guanidine (trifluoroacetic acid salt)(xix-187)

To PS-carbodiimide resin (Argonaut Technologies) (1.069 g, 1.71 mmol,1.6 mmol/g) placed in a 20 mL vial was added anhydrous1,2-dichloroethane (6.0 mL), N,N′-bis(tert-butoxycarbonyl)thiourea (235mg, 0.85 mmol) in anhydrous 1,2-dichloroethane (2.0 mL), and5-amino-3,4-dimethylisoxazole (63.9 mg, 0.57 mmol) solution ordispersion in anhydrous 1,2-dichloroethane (1.0 mL). The reactionmixture was shaken at 50° C. until the reaction completed, typically for36 hours. The reaction mixture was brought to room temperature andPS-trisamine (317 mg, 1.14 mmol, 3.6 mmol/g) was added. The reactionmixture was shaken at room temperature for 24 hours. The resin wasremoved by filtration and washed with 1,2-dichloroethane (3.0 mL) andmethanol (3.0 mL). The combined organic layers were dried in a Genevacat 40° C. The resultant crude reaction mixture was mixed with TFA indichloromethane (25% vol., 5.0 mL) and shaken at room temperature for 6hours followed by evaporation in Genevac 40° C. to give crude xxix-187(152 mg, 99%).: MS m/z=155 (M+H).

Guanidines xix listed in Table 2 were prepared in a manner similar toExample 25, utilizing method U.

TABLE 2 Guanidines

Guanidines xix listed in Table 3 were prepared in a manner similar toMethod S.

TABLE 3 Guanidines

Example 26 Method X for the Synthesis of Sulfonamides

4-[(9-chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(3-morpholin-4-ylpropyl)benzenesulfonamide(I-1279)

To a well in a sealed reaction block containing PL-TPP resins (1.5mmol/g, 200 mg per well, 0.3 mmol per well), was added a mixture ofsulfonic acid (29 mg, 0.07 mmol) and trichloroacetonitrile (40 mg, 0.28mmol) in DMA (2.5 mL). The reaction block was shaken at rt for 1 h. Tothe reaction mixture was added Et₃N (0.07 mL), followed byN-aminopropylmorpholine (14 mg, 0.10 mmol) in DMA (0.3 mL). (Whenlow-boiling amines were used in this Method, 0.35 mmol of the amine wereadded.)

The reaction block was shaken at rt for overnight. The resins were thenfiltered off, and were washed with DMF (2×1.5 mL). The filtrate wasconcentrated in vacuo. The residue was purified by RP-HPLC using anAgilent HPLC equipped with a SunFire™ column (Waters Corporation),Method Formic Acid, or equipped with a Symmetry® column (WatersCorporation), Method Ammonium Acetate, to give compound I-1279 (15.6%):¹H NMR (300 MHz, CD₃OD): δ 8.44 (s, 1H), 8.12 (d, J=8.4 Hz, 1H),7.98-7.94 (m, 2H), 7.75-7.71 (m, 2H), 7.35 (dd, J=2.1, 8.5 Hz, 1H), 7.23(d, J=2.1 Hz, 1H), 3.78 (br. t., 4H), 3.42 (s, 2H), 3.05-3.00 (br. m.,6H), 2.93 (t, J=6.3 Hz, 2H), 1.88-1.78 (m, 2H); MS m/z=543 (M+H).

Example 27 Method Y for Solid Phase Amide Coupling

4-[(9-Chloro-6-oxo-6,7-dihydro-5H-pyrimido[5,4-d][1]benzazepin-2-yl)amino]-N-(4-methoxyphenyl)benzamide(I-555)

To a pre swelled PL-TPP resin [200 mg, 0.3 mmol, (Polymer labs, 1.5mmol/gram loading)] in DMA (1.0 mL) was added a mixture of4-(9-Chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-benzoicacid (I-3) (25 mg 0.066 mmol), DMA (1.5 mL) and trichloroacetonitrile(0.53 mmol). After agitating for three hours at room temperature,triethylamine (46 μL, 0.33 mmol) was added, followed by p-anisidine (8.1mg, 0.066 mmol). The reaction mixture was stirred at 22° C. overnight.The reaction mixture was filtered and the resin was washed with DMF,DMA, and MeOH (1×1 mL). The combined organic layers were concentratedand the crude product was purified by RP-HPLC using an Agilent HPLCequipped with a SunFire™ column (Waters Corporation), Method FormicAcid, to give I-555 (22 mg, 69%). ¹H NMR (DMSO): δ 10.38 (s, 1H), 10.32(s, 1H), 9.93 (s, 1H), 8.59 (s, 1H), 8.10 (d, J=8.9 Hz, 1H), 7.92 (s,1H), 7.64 (d, J=9.3 Hz, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.29 (s, 1H), 6.89(d, J=8.5 Hz, 1H), 3.73 (s, 2H), 3.43 (s, 1H), 3.32 (s, 3H); MSR_(t)=2.70 min (m/z) 466 (M+1).

Example 28 Method for Pd-Mediated Amine Coupling

2-Amino-9-(3-methoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-225)

2-Amino-9-iodo-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (200 mg, 0.568mmol, 1.0 equiv), anhydrous K₃PO₄ powder (241 mg, 1.14 mmol, 2.0 equiv)and palladium bis-tri-t-butyl phosphine (58 mg, 0.1136 mmol, 20 mol %)were combined in a sealable vial with a magnetic stir bar under anitrogen atmosphere (glove box). 3-Methoxyaniline (209 mg, 1.70 mmol,3.0 equiv) was added, followed by 6 mL of anhydrousN-methylpyrrolidinone. The vial was sealed with a silicone lined crimpcap and removed from the glove box. The vial was sonicated for 2 minutesand then heated to 90° C. (oil bath temperature) for 18 hours. The darkbrown solution was diluted with 50 mL of water and the brown solids werecollected by filtration and washed with water and then diethyl ether.Purification by silica gel chromatography (10% methanol, 85%dichloromethane, 5% formic acid) afforded an orange powder, which wasrecrystallized from methanol and diethyl ether to yield 120 mg (61%) of2-amino-9-(3-methoxy-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one(I-225) as a yellow-orange powder.

Example 29 Expression and Purification of Protein Kinase Enzymes

Aurora A Enzyme Expression and Purification

Recombinant mouse Aurora A with an amino-terminus hexahistidine tag(His-Aurora A) was expressed using a standard baculovirus vector andinsect cell expression system (Bac-to-Bac®, Invitrogen).

Soluble, recombinant mouse Aurora A was purified from insect cells usingNi-NTA agarose (Qiagen) as described by the manufacturer and furtherpurified over an S75 size exclusion column (Amersham Pharmacia Biotech).

Aurora B Enzyme Expression and Purification

Recombinant mouse Aurora B with an amino-terminus hexahistidine tag(His-Aurora B) was expressed using a standard baculovirus vector andinsect cell expression system (Bac-to-Bac®, Invitrogen).

Soluble, recombinant mouse Aurora B was purified from insect cells usingNi-NTA agarose (Qiagen) as described by the manufacturer.

Chk-1 Enzyme Expression and Purification:

Recombinant human Chk-1 was expressed as a fusion protein withglutathione S-transferase at the amino-terminus (GST-Chk1) usingstandard baculovirus vectors and (Bac-to-Bac®) insect cell expressionsystem purchased from GIBCO™ Invitrogen. Recombinant protein expressedin insect cells was purified using glutathione sepharose (AmershamBiotech) using standard procedures described by the manufacturer.

PLK1 Enzyme Expression and Purification:

Recombinant human PLK1 was expressed in E. coli as an N-terminal Smtfusion protein using a proprietary vector (pSGX4) by Structural Genomics(SGX). The fusion partner was removed through cleavage with Ulp1 afteran initial purification using a Ni2+ affinity column.

Example 30 Protein Kinase Enzyme Assays

Aurora A DELFIA® Kinase Assay

The mouse Aurora A enzymatic reaction totaled 25 μL and contained 25 mMTris-HCl (pH 8.5), 2.5 mM MgCl₂, 0.05% Surfact-AMPS-20, 5 mM SodiumFluoride, 5 mM DTT, 1 mM ATP, 3 μM peptide substrate(Biotin-β-Ala-QTRRKSTGGKAPR-NH₂), and 20 nM recombinant murine Aurora Aenzyme. The enzymatic reaction mixture, with and without Aurorainhibitors, was incubated for 10 minutes at room temperature beforetermination with 100 μL of stop buffer (1% BSA, 0.05% Surfact-AMPS-20,and 100 mM EDTA). A total of 100 μL of the enzyme reaction mixture wastransferred to wells of a Neutravidin-coated 96-well plate (Pierce) andincubated at room temperature for 30 minutes. The wells were washed withwash buffer (25 mM Tris, 150 mM sodium chloride, and 0.1% Tween 20) andincubated for 1 hour with 100 μL of antibody reaction mixture containing1% BSA, 0.05% Surfact-AMPS-20, anti-phospho-PKA rabbit polyclonalantibody (1:2000, New England Biolabs), and europium labeled anti-rabbitIgG (1:2000, Perkin Elmer). The wells were washed and then the boundeuropium was liberated using 100 μL of Enhancement Solution (PerkinElmer). Quantification of europium was done using a Wallac™ EnVision(Perkin Elmer).

Compounds of the invention were shown to inhibit Aurora A using theassay method described above. For example, compounds I-1 to I-93provided the following test results: I-1 to I-10, I-14 to I-15, I-18,I-24 to I-28, I-30, I-32 to I-33, I-37 to I-42, I-46, to I-47, I-49 toI-50, I-52 to I-57, I-59 to I-60, I-62 to I-67, I-70 to I-73, I-78 toI-79, I-81 to I-82, I-86 to I-89, and I-91 were shown to have IC₅₀values in this assay of less than or equal to 5.0 μM, and compounds I-2,I-3, I-7, I-9, I-10, I-27, I-30, I-32, I-33, I-37, I-38, I-42, I-47,I-49, I-50, I-53, I-57, I-62, I-64, I-66, I-67, I-70, I-71 to I-73,I-82, I-86 to I-89, and I-91 were shown to have IC₅₀ values in thisassay of less than or equal to 0.5 μM.

Aurora B DELFIA® Kinase Assay

The mouse Aurora B enzymatic reaction totaling 25 μL contained 25 mMTris-HCl (pH 8.5), 2.5 mM MgCl₂, 0.025% Surfact-AMPS-20 (Pierce), 1%Glycerol, 1 mM DTT, 1 mM ATP, 3 μM peptide substrate(Biotin-β-Ala-QTRRKSTGGKAPR-NH₂), and 20 nM recombinant murine Aurora Benzyme. The enzymatic reaction mixture, with or without Aurorainhibitors, was incubated for 3 hours at room temperature beforetermination with 100 μL of stop buffer (1% BSA, 0.05% Surfact-AMPS-20,and 100 mM EDTA). A total of 100 mL of the enzyme reaction mixture wastransferred to wells of a Neutravidin-coated 96-well plate (Pierce) andincubated at room temperature for 30 minutes. The wells were washed withwash buffer (25 mM Tris, 150 mM sodium chloride, and 0.1% Tween 20) andincubated for 1 hour with 100 μL of antibody reaction mix containing 1%BSA, 0.05% Surfact-AMPS-20, anti-phospho-PKA rabbit polyclonal antibody(1:2000, New England Biolabs), and europium labeled anti-rabbit IgG(1:2000, Perkin Elmer). The wells were washed and then the boundeuropium was liberated using 100 μL of Enhancement Solution (PerkinElmer). Quantification of europium was done using a Wallac™ EnVision(Perkin Elmer).

Chk-1 DELFIA® Kinase Assay:

Assays (25 μL) utilized 1.94 nM GST-Chk-1 containing 10 mM Tris, pH 7.5,0.1% BSA (TBS), 50 mM NaCl₂, 0.01% Surfact-Amps® 20, 1 μM peptidesubstrate (Biotin-GLYRSPSMPEN-amide), 2 mM DTT, 4% DMSO, 50 or 600 μMATP (depending on potency), 10 mM MgCl₂ and were reacted for 90 minutesat room temperature. Reactions were terminated with 120 μL of Stopbuffer containing 1% BSA (TBS), 100 mM EDTA, pH 8.0, 0.05% Surfact-Amps®20. Stopped reactions (100 μL) were transferred to 96 well neutravidinplates (Pierce) to capture the biotin-peptide substrate during a 45minute room temperature incubation. Wells were washed and reacted with100 μL Perkin-Elmer Wallac™ Assay Buffer containing 22 ng/mLanti-phospho-Ser216-Cdc25c rabbit polyclonal antibody from CellSignaling Technology (Beverly, Mass.) and 405 ng/mL europium labeledanti-rabbit-IgG for 1 hour at room temperature. Wells were washed andeuropium released from the bound antibody by addition of EnhancementSolution (100 μL) (Perkin-Elmer Wallac) and detected using a WallacVictor2™ and standard manufacturer settings.

Compounds of the invention were shown to inhibit Chk-1 using the assaymethod described above. For example, compounds I-1 to I-93 provided thefollowing test results: compounds I-1 to I-3, I-5, I-6, I-9, I-14, I-15,I-18, I-24, I-26, I-27, I-30 to I-33, I-37 to I-42, I-46, I-47, I-49,I-50, I-52 to I-54, I-56, I-57, I-59 to I-67, I-69 to I-73, I-76, I-78,I-79, I-81, I-82, and I-86 to I-92 were shown to have IC₅₀ values inthis assay of less than or equal to 5 μM, and compounds I-1 to I-3, I-9,I-18, I-24, I-27, I-30, I-32, I-33, I-37, I-38, I-41, I-42, I-46, I-47,I-49, I-50, I-52, I-53, I-56, I-57, I-60, I-62 to I-67, I-70 to I-73,I-77 to I-79, I-81, I-82, I-86 to I-89, I-91, and I-92 were shown tohave IC, values in this assay of less than or equal to 0.5 μM.

PLK1 Flash Plate Assay

The human PLK1 enzymatic reaction totaling 30 μL contained 50 mMTris-HCl (pH 8.0), 10 mM MgCl₂, 0.02% BSA, 10% glycerol, 1 mM DTT, 100mM NaCl, 3.3% DMSO, 8 μM ATP, 0.2 μCi [γ-³³P]-ATP, 4 μM peptidesubstrate (Biotin-AHX-LDETGHLDSSGLQEVHLA-CONH₂) and 10 nM recombinanthuman PLK1[2-369]T210D. The enzymatic reaction mixture, with or withoutPLK inhibitors, was incubated for 2.5 hours at 30° C. before terminationwith 20 μL of 150 mM EDTA. 25 μL of the stopped enzyme reaction mixturewas transferred to a 384-well streptavidin coated Image FlashPlate®(Perkin Elmer) and incubated at room temperature for 3 hours. The ImageFlash Plate® wells were washed 3 times with 0.02% Tween-20 and then readon the Perkin Elmer Viewlux™.

Compounds of the invention were shown to inhibit PLK using the assaydescribed above. For example, compounds I-1 to I-93 provided thefollowing test results: compounds I-2, I-3, I-5, I-7 to I-9, I-11 toI-18, I-24 to I-30, I-32 to I-38, I-41, I-42, I-45 to I-47, I-49, I-50,I-52 to I-56, I-65 to I-73, I-78 to I-82, and I-86 to I-89 were shown tohave an IC₅₀ of less than or equal to 5 μM in this assay, and compoundsI-2, I-3, I-5, I-7, I-9, I-11 to I-15, I-18, I-24, I-27 to I-30, I-33 toI-37, I-42, I-45 to I-47, I-49, I-50, I-54 to I-56, I-65 to I-67, I-69,I-70, I-78, I-79, I-81, I-82, and I-86 to I-89 were shown to have anIC₁₀ of less than or equal to 0.5 μM in this assay.

Example 31 Cellular Assay

Aurora Phosphorylation Assays

Inhibition of Aurora A or Aurora B activity in whole cell systems can beassessed by determination of decreased phosphorylation of Aurorasubstrates. For example, determining decreased phosphorylation ofhistone H3 on Serine 10, an Aurora B substrate can be used to measureinhibition of Aurora B activity in a whole cell system. Alternatively,any known Aurora B substrate can be used in similar assay methods toassess inhibition of Aurora B activity. Similarly, Aurora A inhibitioncan be determined using analogous methods and known Aurora A substratesfor detection.

In a specific example, HeLa cells were seeded in a 96-well cell cultureplate (10×10³ cells/well) and incubated overnight at 37° C. Cells wereincubated with Aurora inhibitors for 1 hour at 37° C., fixed with 4%paraformaldehyde for 10 minutes and then permeabilized with 0.5%TritonX-100 in PBS. Cells were incubated with mouse anti-pH is H3(1:120, Cell Signaling Technologies) and rabbit anti-mitotic marker(1:120, Millennium Pharmaceuticals Inc.) antibodies for 1 hour at roomtemperature. After washing with PBS the cells were stained withanti-rabbit IgG Alexa 488 (1:180, Molecular Probes) and anti-mouse IgGAlexa 594 (1:180) for 1 hour at room temperature. DNA was then stainedwith Hoechst solution (2 μg/mL). The percentage of pH is H3 andanti-mitotic positive cells were quantified using Discovery I andMetaMorph (Universal Imaging Corp.). Aurora B inhibition was determinedby calculating the decrease of pH is H3 positive cells.

Anti-Proliferation Assays

HCT-116 (1000) or other tumor cells in 100 μl of appropriate cellculture medium (McCoy's 5A for HCT-116, Invitrogen) supplemented with10% fetal bovine serum (Invitrogen) was seeded in wells of a 96-wellcell culture plate and incubated overnight at 37 C. Test compounds wereadded to the wells and the plates were incubated for 96 hours at 37° C.MTT or WST reagent (10 μl, Roche) was added to each well and incubatedfor 4 hours at 37° C. as described by the manufacturer. For MTT themetabolized dye was solublized overnight according to manufacturer'sinstructions (Roche). The optical density for each well was read at 595nm (primary) and 690 nm (reference) for the MTT and 450 nm for the WSTusing a spectrophotometer (Molecular Devices). For the MTT the referenceoptical density values were subtracted from the values of the primarywavelength. Percent inhibition was calculated using the values from aDMSO control set to 100%.

Anti-Proliferation Assay—Combination of Test Compound and DNA DamagingAgent

HT29, HCT116 (5000 cells/well) or other cells were seeded (75 μL) to 96well clear bottom plates at densities which provide linear growth curvesfor 72 hours. Cells were cultured under sterile conditions inappropriate media; for HT29 and HCT116, this media was McCoy's 5Acontaining 10% Fetal Bovine Serum (FBS). Following the initial seedingof cells they were incubated at 37° C., 5% CO₂ from 17 to 24 hours atwhich time the appropriate DNA damaging agents (camptothecins,5-fluorouracil, doxorubicin, and etoposide) were added at increasingconcentrations to a point which is capable of causing at least 80% cellkilling with in 48 hours. Final volume of all DNA damaging agent andtest compound additions was 25 μL and assays contained <1% DMSO final.At the same time as DNA damaging agent addition, the test compound wasadded at fixed concentrations to each DNA damaging agent titration toobserve enhancement of cell killing. In addition, toxicity of each testcompound alone was observed. By doing this over a range of test compoundconcentrations, compounds were identified which maximally enhance (2-30fold) cell killing by each DNA damaging agent and generated ≦80% cellkilling by the compound alone. Cell viability/cell killing under theconditions described above was determined by addition WST reagent(Roche) according to the manufacturer at 47 hours following DNA damage &Chk-1 inhibitor addition and following a 3.5 hour or 2.5 hour incubationat 37 C, 5% CO₂, OD₄₅₀, was measured.

Example 32 In Vivo Assays

In Vivo Tumor Efficacy Model

HCT-116 (1×10⁶) or other tumor cells in 100 μL of phosphate bufferedsaline are aseptically injected into the subcutaneous space in the rightdorsal flank of female CD-1 nude mice (age 5-8 weeks, Charles River)using a 23-ga needle. Beginning at day 7 after inoculation tumors aremeasured twice weekly using a vernier caliper. Tumor volumes arecalculated using standard procedures (0.5×(length×width²)). When thetumors reach a volume of approximately 200 mm³ mice are injected i.v. inthe tail vein with test compound (100 μL) at various doses andschedules. All control groups receive vehicle alone. Tumor size and bodyweight are measured twice a week and the study is terminated when thecontrol tumors reach approximately 2000 mm³.

In Vivo Tumor Efficacy Model—Combination of Test Compound and DNADamaging Agent

HT29 human colon cancer cells with p53 deficiency are cultured with 10%FBS in McCoy's 3A medium and incubated at 5% CO₂. The cells aretrypsinized and resuspended in Hanks buffer at 2×10⁷ cells/mL. 100 μL ofthe cell suspension (2×10⁶ cells) is aseptically implanted into thesubcutaneous space in the right dorsal flank of male NCR nude mice (age5-8 weeks, Taconic) using a 23-ga needle. Seven days after implantation,the tumors are measured in two dimensions (length and width) with acaliper and the animal body weight is measured with a balance. Tumorvolume is calculated with the following formula: tumor volume=L×W²×0.5.When the average tumor volume reaches about 200 mm³, the individualanimals are assigned to different study groups using a random numbergeneration method. The typical study consists of vehicle control, CPT-11alone (i.v.), Chk-1 inhibitor alone (i.p.), and CPT-11 in combinationwith Chk-1 inhibitor groups at various doses and schedules. Tumor sizeand body weight are measured twice a week for four weeks. Once the tumorvolume reaches over 10% of the body weight of the animal, or the mousebody weight loss is more than 20%, the mouse is euthanized. Data iscollected only from those study groups in which there are five or moreanimals.

While the foregoing invention has been described in some detail forpurposes of clarity and understanding, these particular embodiments areto be considered as illustrative and not restrictive. It will beappreciated by one skilled in the art from a reading of this disclosurethat various changes in form and detail can be made without departingfrom the true scope of the invention, which is to be defined by theappended claims rather than by the specific embodiments.

The patent and scientific literature referred to herein establishesknowledge that is available to those with skill in the art. Unlessotherwise defined, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this invention belongs. The issued patents, applications,and references that are cited herein are hereby incorporated byreference to the same extent as if each was specifically andindividually indicated to be incorporated by reference. In the case ofinconsistencies, the present disclosure, including definitions, willcontrol.

1. A method for treating colon cancer in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof; wherein: Ring A is anoptionally substituted 5- or 6-membered aryl or heteroaryl ring; G¹ isC═O, C═S, or S(═O)₂; Y¹ is N or CH and Y² is N or CR^(e), provided thatat least one of Y¹ and Y² is N; R^(a) is hydrogen, —C(O)R^(5a),C(O)N(R^(4a))₂, —CO₂R^(6a), —SO₂R^(6a), —SO₂N(R⁴)₂, an optionallysubstituted C₁₋₁₀ aliphatic, or an optionally substituted aryl,heteroaryl, or heterocyclyl ring; R^(b) is hydrogen or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; R^(c) ishydrogen, fluoro, —OR⁵, —N(R⁴)₂, or an optionally substitutedC₁₋₄aliphatic; R^(d) is hydrogen, fluoro, C₁₋₄-aliphatic orC₁₋₄fluoroaliphatic; or R^(c) and R^(d), taken together with the carbonatom to which they are attached, form an optionally substituted 3- to6-membered carbocyclic ring; R^(e) is hydrogen, halo, —NO₂, —CN,—C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R¹⁰, —OR⁵, —N(R⁴)₂,—NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —CO₂R⁵, —C(O)R⁵, —C(O)N(R⁴)₂,—N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, or an optionally substitutedC₁₋₄aliphatic; each R⁴ independently is hydrogen or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or twoR⁴ on the same nitrogen atom, taken together with the nitrogen atom,form an optionally substituted 4- to 8-membered heterocyclyl ringhaving, in addition to the nitrogen, atom, 0-2 ring heteroatoms selectedfrom N, O, and S; each R^(4a) independently is hydrogen or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; or twoR^(4a) on the same nitrogen atom, taken together with the nitrogen atom,form an optionally substituted 4- to 8-membered heterocyclyl ringhaving, in addition to the nitrogen atom, 0-2 ring heteroatoms selectedfrom N, O, and S; each R⁵ independently is hydrogen or an optionallysubstituted aliphatic, aryl, heteroaryl, or heterocyclyl group; eachR^(5a) independently is hydrogen or an optionally substituted aliphatic,aryl, heteroaryl, or heterocyclyl group; each R⁶ independently is anoptionally substituted aliphatic or aryl group; each R^(6a)independently is an optionally substituted aliphatic or aryl group; andR¹⁰ is —CO₂R⁵ or —C(O)N(R⁴)₂.
 2. The method of claim 1, furthercomprising administering to the patient a cytotoxic agent selected fromthe group consisting of chemotherapeutic agents and radiation therapy.3. The method of claim 1, wherein the compound is characterized by oneor more of the following features (a)-(e): a. Y¹ is N; b. Y² is CR^(e),where R^(e) is selected from the group consisting of hydrogen,C₁₋₄aliphatic, C₁₋₄fluoroaliphatic, -halo, —OR⁵, —N(R⁴)₂, —CN, —CO₂R⁵,—C(O)N(R⁴)₂, —C(R⁵)═C(R⁵)₂, —C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R⁵, and —C≡C—R¹⁰; c.G¹ is C═O; d. R^(c) is selected from the group consisting of hydrogen,fluoro, —OR⁵, —N(R⁴)₂, and C₁₋₄aliphatic optionally substituted with oneor two groups independently selected from C₁₋₃aliphatic, fluoro, —OR⁵,—N(R⁴)₂, —CO₂R⁵, —C(O)N(R⁴)₂, and optionally substituted 5- or6-membered aryl or heteroaryl; and e. R^(d) is hydrogen.
 4. The methodof claim 1, wherein in the compound Ring A is a substituted orunsubstituted 5- or 6-membered aryl or heteroaryl ring selected from thegroup consisting of furano, thieno, pyrrolo, oxazolo, thiazolo,imidazolo, pyrazolo, isoxazolo, isothiazolo, oxadiazolo, triazolo,thiadiazolo, benzo, pyridino, pyridazino, pyrimidino, pyrazino, andtriazine.
 5. The method of claim 4, wherein in the compound: Ring A issubstituted with 0-2 R^(h) and 0-2 R^(8h); each R^(h) independently isselected from the group consisting of C₁₋₆aliphatic,C₁₋₆fluoroaliphatic, halo, —R^(1h), —R^(2h), -T⁴-R^(2h), -T⁴-R^(1h),—V³-T⁴-R^(1h), and —V³-T⁴-R^(2h), or two adjacent R^(h), taken togetherwith the intervening ring atoms, form an optionally substituted fused 4-to 8-membered aromatic or non-aromatic ring having 0-3 ring heteroatomsselected from the group consisting of O, N, and S; T⁴ is a C₁₋₆alkylenechain optionally substituted with one or two independently selectedR^(3a) or R^(3b), wherein the alkylene chain optionally is interruptedby —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—, —N(R⁴)—,—N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—, —C(O)N(R⁴)—, —C(O)—,—C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, —OC(O)N(R⁴)—, —N(R⁴)SO₂—, or—SO₂N(R⁴); V³ is —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—,—SO₂N(R⁴)—, —N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—,—C(O)N(R⁴)—, —C(O)—, —C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—,—OC(O)N(R⁴)—, —C(NR⁴)═N—, —C(OR⁵)═N—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—,—P(O)(R⁵)—, —P(O)(OR⁵)—O—, —P(O)—O—, or —P(O)(NR⁵)—N(R⁵)—; each R^(1h)independently is an optionally substituted aryl, heteroaryl,heterocyclyl, or cycloaliphatic ring; each R^(2h) independently is —NO₂,—CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R¹⁰, —OR⁵, —SR⁶,—S(O)R⁶, —SO₂R⁶, SO₃R⁵, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂,—NR⁴CO₂R⁶, —O—CO₂R⁵, —OC(O)N(R⁴)₂, —O—C(O)R⁵, —CO₂R⁵, —C(O)—C(O)R⁵,—C(O)R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O), —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵, —C(R⁶)═N—OR⁵,—N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —P(O)(R⁵)₂, or—P(O)(OR⁵)₂; each R^(3a) independently is selected from the groupconsisting of —F, —OH, —O(C₁₋₃alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₃alkyl),—CO₂H, —CO₂(C₁₋₃alkyl), —C(O)NH₂, and —C(O)NH(C₇₋₃alkyl); each R^(3b)independently is a C₁₋₃aliphatic optionally substituted with R^(3a) orR⁷, or two substituents R^(3b) on the same or adjacent carbon atom(s),taken together with the carbon atom(s) to which they are attached, forma 3- to 6-membered carbocyclic ring; each R⁷ independently is anoptionally substituted aryl or heteroaryl ring; and each R^(8h)independently is selected from the group consisting of C₁₋₄aliphatic,C₁₋₄fluoroaliphatic, -halo, and —O(C₁₋₄aliphatic).
 6. The method ofclaim 5, wherein the compound is represented by the structure of formula(II):

or a pharmaceutically acceptable salt thereof; wherein Ring A issubstituted with 0-2 R^(h) and 0-2 R^(8h).
 7. The method of claim 6,wherein in the compound Ring A is substituted with 0-2 R^(8h)substituents independently selected from the group consisting ofC₁₋₄aliphatic, C₁₋₄fluoroaliphatic, -halo, and —O(C₁₋₄aliphatic), or twoadjacent substituents, taken together with the intervening ring atoms,form a fused dioxolane or dioxane ring.
 8. The method of claim 6,wherein in the compound Ring A has the formula A-i, A-ii, or A-iii:

wherein m is 0, 1, or
 2. 9. The method of claim 7, wherein in thecompound R^(h) is —CN, —CO₂R⁵, —C(O)N(R⁴)₂, —N(R⁴)₂, or —OR⁵.
 10. Themethod of claim 7, wherein: R^(h) is -T⁴-R^(2h), —V³-T⁴-R^(2h), or-Cy-T⁴-R^(2h); V³ is —C≡C—, —C(R⁵)═C(R⁵)—, or —C(O)N(R⁴)—; Cy is a 5- or6-membered arylene or heteroarylene; T⁴ is a C₁₋₄alkylene chain; andR^(2h) is —OR⁵, —N(R⁴)₂, or —C(O)N(R⁴)₂.
 11. The method of claim 10,wherein in the compound R^(b) is hydrogen.
 12. The method of claim 1,wherein in the compound R^(a) is hydrogen, C₁₋₆aliphatic, -T¹¹-R^(1a),-T¹¹-R^(21a), -T¹²-R^(22a), —V¹-T11-R^(1a), —V¹-T¹¹-R^(21a),—V¹-T¹¹-R^(22a), or —R^(1a); V¹ is —C(O)—, —C(O)N(R^(4a))—, —C(O)O—,—SO₂—, or —SO₂N(R^(4a))—; T¹¹ is a C₁₋₆alkylene chain optionallysubstituted with one or two independently selected R^(3a) or R^(3b),wherein the alkylene chain optionally is interrupted by —C(R⁵)═C(R⁵)— or—C≡C—; T¹² is a C₂₋₆alkylene chain optionally substituted with one ortwo independently selected R^(3a) or R^(3b), wherein the alkylene chainoptionally is interrupted by —C(R⁵)═C(R⁵)— or —C≡C—; each R^(3a)independently is selected from the group consisting of —F, —OH,—O(C₁₋₃alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₃alkyl), —CO₂H, —CO₂(C₁₋₃alkyl),—C(O)NH₂, and —C(O)NH(C₁₋₃alkyl); each R^(3b) independently is aC₁₋₃aliphatic optionally substituted with R³″ or R⁷, or two substituentsR^(3b) on the same or adjacent carbon atom(s), taken together with thecarbon atom(s) to which they are attached, form a 3- to 6-memberedcarbocyclic ring; R^(21a) is —C(R^(5a))═C(R^(5a))₂, —C≡C—R^(5a),—S(O)R^(6a), —SO₂R^(6a), —SO₃R^(5a), —SO₂N(R^(4a))₂, —CO₂R^(5a),—C(O)—C(O)R^(5a), —C(O)R^(5a), —C(O)N(R^(4a))₂,—C(O)N(R^(4a))C(═NR^(4a))—N(R^(4a))₂, —C(═NR^(4a))—N(R^(4a))₂,—C(═NR^(4a))—OR^(5a), —C(R^(6a))═N—OR^(5a), —P(O)(R^(5a))₂, or—P(O)(OR^(5a))₂; R^(22a) is —NO₂, —CN, —OR^(5a), —SR^(6a), —N(R^(4a))₂,—NR^(4a)C(O)R^(5a), —NR^(4a)C(O)N(R^(4a))₂, —NR^(4a)CO₂R^(6a),—O—CO₂R^(5a), —OC(O)N(R^(4a))₂, —O—C(O)R^(5a),—N(R^(4a))C(═NR^(4a))—N(R^(4a))₂,—N(R^(4a))C(═NR^(4a))—N(R^(4a))—C(O)R⁵, —N(R^(4a))SO₂R^(6a), or—N(R^(4a))SO₂N(R^(4a))₂; each R⁷ independently is an optionallysubstituted aryl or heteroaryl ring; and R^(1a) is an optionallysubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring. 13.The method of claim 12, wherein the compound is represented by formula(III):

or a pharmaceutically acceptable salt thereof; wherein Ring B issubstituted with 0-2 R^(j) and 0-2 R^(8j), each R^(j) independently isselected from the group consisting of C₁₋₆aliphatic,C₁₋₆fluoroaliphatic, halo, —R^(1j), —R^(2j), -T⁵-R^(2j), -T⁵-R^(1j),—V⁴-T⁵-R^(1j), and —V⁴-T⁵-R^(2j); or two adjacent R^(j), taken togetherwith the intervening ring atoms, form an optionally substituted fused 4-to 8-membered aromatic or non-aromatic ring having 0-3 ring heteroatomsselected from the group consisting of O, N, and S; T⁵ is a C₁₋₆alkylenechain optionally substituted with one or two independently selectedR^(3a) or R^(3b), wherein the alkylene chain optionally is interruptedby —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—, —N(R⁴)—,—N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—, —C(O)N(R⁴)—, —C(O)—,—C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, —OC(O)N(R⁴)—, —N(R⁴)SO₂—, or—SO₂N(R⁴); V⁴ is —C(R⁵)═C(R⁵)—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—,—N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—, —C(O)N(R⁴)—, —C(O)—,—C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, —OC(O)N(R⁴)—, —C(NR⁴)═N—,—C(OR⁵)═N—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—, —P(O)(R⁵)—, —P(O)(OR⁵)—O—,—P(O)—O—, or —P(O)(NR⁵)—N(R⁵)—; each R^(1j) independently is anoptionally substituted aryl, heteroaryl, heterocyclyl, or cycloaliphaticring; each R^(2j) independently is —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵,—C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R¹⁰, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₃R⁵,—SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —O—CO₂R⁵,—OC(O)N(R⁴)₂, —O—C(O)R⁵, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵, —C(O)N(R⁴)₂,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O), —C(═NR⁴)—N(R⁴)₂,—C(═NR⁴)—OR⁵, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂,—P(O)(R⁵)₂, or —P(O)(OR⁵)₂; each R^(3a) independently is selected fromthe group consisting of —F, —OH, —CN, —N(R⁴)₂, —C(O)(C₁₋₃alkyl), —CO₂H,—CO₂(C₁₋₃ alkyl), —C(O)NH₂, and —C(O)NH(C₁₋₃alkyl); each R^(3b)independently is a C₁₋₃aliphatic optionally substituted with R^(3a) orR⁷, or two substituents R^(3b) on the same or adjacent carbon atom(s),taken together with the carbon atom(s) to which they are attached, forma 3- to 6-membered carbocyclic ring; each R⁷ independently is anoptionally substituted aryl or heteroaryl ring; and each R^(8j)independently is selected from the group consisting of C₁₋₄aliphatic,C₁₋₄fluoroaliphatic, -halo, —CO₂H, —CO₂(C₁₋₄aliphatic), —OH, and—O(C₁₋₄aliphatic).
 14. The method of claim 13, wherein in the compoundRing B has the formula B-i, B-ii, or B-iii:

wherein n is 0, 1, or
 2. 15. The method of claim 14, wherein in thecompound: R^(j) is -T⁵-R^(2j) or —V⁴-T⁵-R^(2j); V⁴ is —C≡C—, or—C(R⁵)═C(R⁵)—; and R^(2j) is —OR⁵ or —N(R⁴)₂.
 16. The method of claim14, wherein in the compound R^(j) is —V⁴-T⁵-R^(2j) or —V⁴-T⁵-R^(1j); V⁴is —C(O)N(R⁴)— or —SO₂N(R⁴)—; and T⁵ is a C₂₋₄alkylene chain, optionallysubstituted with —F or C₁₋₄aliphatic.
 17. The method of claim 1, whereinin the compound R^(b) is hydrogen or C₁₋₆aliphatic.
 18. The method ofclaim 1, wherein in the compound: R^(b) is -T²¹-R^(1b), -T²¹-R^(21b), or-T²²-R^(22b); T²¹ is a C₁₋₆alkylene chain optionally substituted withone or two R³, wherein the alkylene chain optionally is interrupted by—C(R⁵)═C(R⁵)— or —C≡C—; T²² is a C₂₋₆alkylene chain optionallysubstituted with one or two R³, wherein the alkylene chain optionally isinterrupted by —C(R⁵)═C(R⁵)— or —C≡C—; R^(1b) is an optionallysubstituted aryl, heteroaryl, heterocyclyl, or cycloaliphatic ring; eachR³ independently is selected from the group consisting of C₁₋₃aliphatic,-fluoro, —OH, and —O(C₁₋₃ alkyl), or two substituents R³ on the samecarbon atom, taken together with the carbon atom to which they areattached, form a 3- to 6-membered carbocyclic ring; and R^(21b) is—C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R¹⁰, —S(O)R⁶, —SO₂R⁶,—SO₃R⁵, —SO₂N(R⁴)₂, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵, —C(O)N(R⁴)₂,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵, —C(R⁶)═N—OR⁵,—P(O)(R⁵)₂, or —P(O)(OR⁵)₂; R^(22b) is —NO₂, —CN, —OR⁵, —SR⁶, —N(R⁴)₂,—NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —O—CO₂R⁵, —OC(O)N(R⁴)₂,—O—C(O)R⁵, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O)R⁵,—N(R⁴)SO₂R⁶, or —N(R⁴)SO₂N(R⁴)₂.
 19. The method of claim 1, wherein inthe compound R^(b) is an optionally substituted aryl, heteroaryl, orheterocyclyl ring.
 20. The method of claim 19, wherein the compound isrepresented by formula (IV)

or a pharmaceutically acceptable salt thereof; wherein Ring C issubstituted with 0-2 R^(k) and 0-2 R^(8k); each R^(k) independently isselected from the group consisting of C₁₋₆aliphatic,C₁₋₆fluoroaliphatic, -halo, —R^(1k), —R^(2k), -T⁶-R^(2k), -T⁶-R^(1k),—V⁵-T⁶-R^(1k), and —V⁵-T⁶-R^(2k); or two adjacent R^(k), taken togetherwith the intervening ring atoms, form an optionally substituted fused 4-to 8-membered aromatic or non-aromatic ring having 0-3 ring heteroatomsselected from the group consisting of O, N, and S; T⁶ is a C₁₋₆alkylenechain optionally substituted with one or two independently selectedR^(3a) or R^(3b), wherein the alkylene chain optionally is interruptedby —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—, —N(R⁴)—,—N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—, —C(O)N(R⁴)—, —C(O)—,—C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, —OC(O)N(R⁴)—, —N(R⁴)SO₂—, or—SO₂N(R⁴); V⁵ is —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—,—SO₂N(R⁴)—, —N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—,—C(O)N(R⁴)—, —C(O)—, —C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—,—OC(O)N(R⁴)—, —C(NR⁴)═N—, —C(OR⁵)═N—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—,—P(O)(R⁵)—, —P(O)(OR⁵)—O—, —P(O)—O—, or —P(O)(NR⁵)—N(R⁵)—; each R^(1k)independently is an optionally substituted aryl, heteroaryl,heterocyclyl, or cycloaliphatic ring; each R^(2k) independently is —NO₂,—CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R¹⁰, —OR⁵, —SR⁶,—S(O)R⁶, —SO₂R⁶, —SO₃R⁵, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵,—NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —O—CO₂R⁵, —OC(O)N(R⁴)₂, —O—C(O)R⁵, —CO₂R⁵,—C(O)—C(O)R⁵, —C(O)R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O), —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,—N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —P(O)(R⁵)₂, or—P(O)(OR⁵)₂; each R^(3a) independently is selected from the groupconsisting of —F, —OH, —O(C₁₋₃alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₃alkyl),—CO₂H, —CO₂(C₁₋₃alkyl), —C(O)NH₂, and —C(O)NH(C₁₋₃alkyl); each R^(3b)independently is a C₁₋₃aliphatic optionally substituted with R^(3a) orR⁷, or two substituents R^(3b) on the same or adjacent carbon atom(s),taken together with the carbon atom(s) to which they are attached, forma 3- to 6-membered carbocyclic ring; each R⁷ independently is anoptionally substituted aryl or heteroaryl ring; and each R^(8k)independently is selected from the group consisting of C₁₋₄aliphatic,C₁₋₄fluoroaliphatic, -halo, and —O(C₁₋₄aliphatic).
 21. The method ofclaim 20, wherein in the compound Ring C is substituted with 0-2substituents independently selected from the group consisting ofC₁₋₄aliphatic, C₁₋₄fluoroaliphatic, -halo, and —O(C₁₋₄aliphatic).
 22. Amethod for treating colon cancer in a patient in need thereof,comprising administering to the patient a therapeutically effectiveamount of a compound of formula (V):

or a pharmaceutically acceptable salt thereof; wherein: Ring A issubstituted with 0-2 R^(h) and 0-2 R^(8h); Ring B is substituted with0-2 R^(j) and 0-2 R^(8j); G is C═O, C═S, or S(═O)₂; Y¹ is N or CH; Y² isN or CR^(e); R^(b) is hydrogen or an optionally substituted aliphatic,aryl, heteroaryl, or heterocyclyl group; R^(c) is hydrogen, fluoro,—OR⁵, —N(R⁴)₂, or an optionally substituted C₁₋₄aliphatic; R^(d) ishydrogen, fluoro, or C₁₋₄aliphatic; or R^(c) and R^(d), taken togetherwith the carbon atom to which they are attached, form an optionallysubstituted 3- to 6-membered carbocyclic ring; R^(e) is hydrogen, halo,C₁₋₄aliphatic, C₁₋₄fluoroaliphatic, —R^(2e), -T³-R^(1e), -T³-R^(2e),—V²-T³-R^(1e), or —V²-T³-R^(2e); T³ is a C₁₋₄alkylene chain optionallysubstituted with one or two R³; V² is —C(R⁵)═C(R⁵)— or —C≡C—; R^(1e) isan optionally substituted aryl, heteroaryl, heterocyclyl, orcycloaliphatic ring; R^(2e) is —NO₂, —CN, —C(R⁵)═C(R⁵)₂,—C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R⁵, —C≡C—R¹⁰, —OR⁵, —N(R⁴)₂, —NR⁴C(O)R⁵,—NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —CO₂R⁵, —C(O)R⁵, —C(O)N(R⁴)₂, —N(R⁴)SO₂R⁶, or—N(R⁴)SO₂N(R⁴)₂; each R^(h) independently is selected from the groupconsisting of C₁₋₆aliphatic, C₁₋₆fluoroaliphatic, halo, —R^(1h),—R^(2h), -T⁴-R^(2h), -T⁴-R^(1h), —V³-T⁴-R^(1h), and —V³-T⁴-R^(2h), ortwo adjacent R^(h), taken together with the intervening ring atoms, forman optionally substituted fused 4- to 8-membered aromatic ornon-aromatic ring having 0-3 ring heteroatoms selected from the groupconsisting of O, N, and S; T⁴ is a C₁₋₆alkylene chain optionallysubstituted with one or two independently selected R^(3a) or R^(3b),wherein the alkylene chain optionally is interrupted by —C(R⁵)═C(R⁵)—,—C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—, —N(R⁴)—, —N(R⁴)C(O)—,—NR⁴C(O)N(R⁴—, —N(R⁴)CO₂—, —C(O)N(R⁴)—, —C(O)—, —C(O)—C(O)—, —CO₂—,—OC(O)—, —OC(O)O—, —OC(O)N(R⁴)—, —N(R⁴)SO₂—, or —SO₂N(R⁴); V³ is—C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—, —N(R⁴)—,—N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—, —C(O)N(R⁴)—, —C(O)—,—C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, —OC(O)N(R⁴)—, —C(NR⁴)═N—,—C(OR⁵)═N—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—, —P(O)(R⁵)—, —P(O)(OR⁵)—O—,—P(O)—O—, or —P(O)(NR⁵)—N(R⁵)—; each R^(1h) independently is anoptionally substituted aryl, heteroaryl, heterocyclyl, or cycloaliphaticring; each R^(2h) independently is —NO₂, —CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵,—C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R¹⁰, —OR⁵, —SR⁶, —S(O)R⁶, —SO₂R⁶, —SO₃R⁵,—SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵, —NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —O—CO₂R⁵,—OC(O)N(R⁴)₂, —O—C(O)R⁵, —CO₂R⁵, —C(O)—C(O)R⁵, —C(O)R⁵, —C(O)N(R⁴)₂,—C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)C(═NR⁴)—N(R⁴)—C(O), —C(═NR⁴)—N(R⁴)₂,—C(═NR⁴)—OR⁵, —C(R⁶)═N—OR⁵, —N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)SO₂R⁶,—N(R⁴)SO₂N(R⁴)₂, —P(O)(R⁵)₂, or —P(O)(OR⁵)₂; each R^(j) independently isselected from the group consisting of C₁₋₆aliphatic,C₁₋₆fluoroaliphatic, halo, —R^(1j), —R^(2j), -T⁵-R^(2j), -T⁵-R^(1j),—V⁴-T⁵-R^(1j), and —V⁴-T⁵-R^(2j); or two adjacent R^(j), taken togetherwith the intervening ring atoms, form an optionally substituted fused 4-to 8-membered aromatic or non-aromatic ring having 0-3 ring heteroatomsselected from the group consisting of O, N, and S; T⁵ is a C₁₋₆alkylenechain optionally substituted with one or two independently selectedR^(3a) or R^(3b), wherein the alkylene chain optionally is interruptedby —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—, —SO₂N(R⁴)—, —N(R⁴)—,—N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—, —C(O)N(R⁴)—, —C(O)—,—C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—, —OC(O)N(R⁴)—, —N(R⁴)SO₂—, or—SO₂N(R⁴); V⁴ is —C(R⁵)═C(R⁵)—, —C≡C—, —O—, —S—, —S(O)—, —S(O)₂—,—SO₂N(R⁴)—, —N(R⁴)—, —N(R⁴)C(O)—, —NR⁴C(O)N(R⁴)—, —N(R⁴)CO₂—,—C(O)N(R⁴)—, —C(O)—, —C(O)—C(O)—, —CO₂—, —OC(O)—, —OC(O)O—,—OC(O)N(R⁴)—, —C(NR⁴)═N—, —C(OR⁵)═N—, —N(R⁴)SO₂—, —N(R⁴)SO₂N(R⁴)—,—P(O)(R⁵)—, —P(O)(OR⁵)—O—, —P(O)—O—, or —P(O)(NR⁵)—N(R⁵)—; each R^(1j)independently is an optionally substituted aryl, heteroaryl,heterocyclyl, or cycloaliphatic ring; each R^(2j) independently is —NO₂,—CN, —C(R⁵)═C(R⁵)₂, —C≡C—R⁵, —C(R⁵)═C(R⁵)(R¹⁰), —C≡C—R¹⁰, —OR⁵, —SR⁶,—S(O)R⁶, —SO₂R⁶, —SO₃R⁵, —SO₂N(R⁴)₂, —N(R⁴)₂, —NR⁴C(O)R⁵,—NR⁴C(O)N(R⁴)₂, —NR⁴CO₂R⁶, —O—CO₂R⁵, —OC(O)N(R⁴)₂, —O—C(O)R⁵, —CO₂R⁵,—C(O)—C(O)R⁵, —C(O)R⁵, —C(O)N(R⁴)₂, —C(O)N(R⁴)C(═NR⁴)—N(R⁴)₂,—N(R⁴)C(═NR⁴)—N(R⁴)—C(O), —C(═NR⁴)—N(R⁴)₂, —C(═NR⁴)—OR⁵,—N(R⁴)C(═NR⁴)—N(R⁴)₂, —N(R⁴)SO₂R⁶, —N(R⁴)SO₂N(R⁴)₂, —P(O)(R⁵)₂, or—P(O)(OR⁵)₂; each R³ independently is selected from the group consistingof C₁₋₃aliphatic, —F, —OH, and —O(C₁₋₃alkyl), or two substituents R³ onthe same carbon atom, taken together with the carbon atom to which theyare attached, form a 3- to 6-membered carbocyclic ring; each R^(3a)independently is selected from the group consisting of —F, —OH,—O(C₁₋₃alkyl), —CN, —N(R⁴)₂, —C(O)(C₁₋₃alkyl), —CO₂H, —CO₂(C₁₋₃alkyl),—C(O)NH₂, and —C(O)NH(C₁₋₃alkyl); each R^(3b) independently is aC₁₋₃aliphatic optionally substituted with R^(3a) or R⁷, or twosubstituents R^(3b) on the same or adjacent carbon atom(s), takentogether with the carbon atom(s) to which they are attached, form a 3-to 6-membered carbocyclic ring; and each R⁴ independently is hydrogen oran optionally substituted aliphatic, aryl, heteroaryl, or heterocyclylgroup; or two R⁴ on the same nitrogen atom, taken together with thenitrogen atom, form an optionally substituted 4- to 8-memberedheterocyclyl ring having, in addition to the nitrogen atom, 0-2 ringheteroatoms selected from N, O, and S; each R^(4a) independently ishydrogen or an optionally substituted aliphatic, aryl, heteroaryl, orheterocyclyl group; or two R^(4a) on the same nitrogen atom, takentogether with the nitrogen atom, form an optionally substituted 4- to8-membered heterocyclyl ring having, in addition to the nitrogen atom,0-2 ring heteroatoms selected from N, O, and S; each R⁵ independently ishydrogen or an optionally substituted aliphatic, aryl, heteroaryl, orheterocyclyl group; each R^(5a) independently is hydrogen or anoptionally substituted aliphatic, aryl, heteroaryl, or heterocyclylgroup; each R⁶ independently is an optionally substituted aliphatic oraryl group; each R^(6a) independently is an optionally substitutedaliphatic or aryl group; each R⁷ independently is an optionallysubstituted aryl or heteroaryl ring; each R^(8h) independently isselected from the group consisting of C₁₋₄aliphatic,C₁₋₄fluoroaliphatic, -halo, and —O(C₁₋₄aliphatic); each R^(8j)independently is selected from the group consisting of C₁₋₄aliphatic,C₁₋₄fluoroaliphatic, -halo, —CO₂H, —CO₂(C₁₋₄aliphatic), —OH, and—O(C₁₋₄aliphatic); and R¹⁰ is —CO₂R⁵ or —C(O)N(R⁴)₂.